Transcriptional Control of The Inflammatory Response PDF

REVIEWS
Transcriptional control of the

inflammatory response
Ruslan Medzhitov* and Tiffany Horng
Abstract | Inflammation is a multicomponent response to tissue stress, injury and infection,

and a crucial point of its control is at the level of gene transcription. The inducible
inflammatory gene expression programme such as that triggered by Toll-like receptor
signalling in macrophages is comprised of several coordinately regulated sets of genes
that encode key functional programmes; these are controlled by three classes of
transcription factors, as well as various transcriptional co-regulators and chromatin
modifications. Here, we discuss the mechanisms of and the emerging principles in the
transcriptional regulation of inflammatory responses in diverse physiological settings.
*Howard Hughes Medical

Institute and Department of
Immunobiology, Yale
University School of
Medicine, New Haven,
Connecticut 06510, USA.
Department of Genetics
and Complex Diseases,
Harvard School of Public
Health, Boston,
Massachusetts 02115, USA.
e-mails:
ruslan.medzhitov@yale.edu;
thorng@hsph.harvard.edu
doi:10.1038/nri2634
Inflammation is a fundamental adaptation to the loss

of cellular and tissue homeostasis with many important
physiological roles, including host defence, tissue remodelling and repair, and the regulation of metabolism13. The
complexity of the inflammatory response requires that its
many functional programmes are controlled coordinately
in some situations but independently in others. This is
achieved through multiple mechanisms that operate at
different levels, including alterations in the composition
of immune cells in tissues, changes in cell responsiveness
to inflammatory stimuli, regulation of signalling pathways and control at the level of gene expression. So, the
mechanisms that regulate inflammatory responses can be
divided into cell-specific, signal-specific and gene-specific
mechanisms. Cell-specific mechanisms operate at the
level of different cell types, and include regulation of their
recruitment and activation. Signal-specific mechanisms
operate at the level of signalling pathways: for example,
by terminating activation of the key transcription factor
nuclear factor-B (NF-B) as a part of a negative feedback
mechanism. Finally, gene-specific mechanisms operate at
the level of individual genes and gene subsets. For example, interleukin-10 (IL-10) and many nuclear receptors
negatively regulate the transcription of specific subsets
of inflammatory genes. As such, gene-specific mechanisms are particularly well suited to provide functional
specificity in an inflammatory response. Here, we review
the recent progress in understanding the transcriptional
regulation of the inflammatory response. In addition, we
discuss the key factors and molecular mechanisms that
regulate inflammatory gene expression, with the objective of defining some general principles that govern this
important physiological process.
Macrophages are crucial mediators of the inflammatory response, and Toll-like receptors (TLRs) are
the best-characterized inducers of acute inflammation.
Therefore, much of this Review focuses on the transcriptional regulation of inflammation by TLR ligands
and in particular by lipopolysaccharide (LPS) in
macrophages. After only a few hours of LPS stimulation, the expression of several hundred genes is induced
(and repressed) in macrophages4,5. This is a complex
transcriptional response, consisting of multiple gene
sets that encode functional programmes controlling cell
migration, tissue repair and remodelling, antimicrobial
defence, phagocytosis, metabolic reprogramming and
the regulation of adaptive immune responses. These
gene sets, or transcriptional modules, are often coordinately regulated by dedicated transcription factors. This
feature of the transcriptional response enables autonomous control of individual transcriptional modules,
because the transcriptional regulators that control their
expression can be differentially regulated by positive and
negative signals (BOX 1).
Several examples of transcriptional regulators that
control distinct transcriptional modules are currently
known, both within and outside of the LPS-induced
transcriptional response. These include class II transactivator (CIITA), which is a master regulator of genes
involved in the MHC class II-restricted pathway of
antigen processing and presentation6; interferon (IFN)stimulated gene factor 3 (ISGF3), which controls the
expression of type I IFN-induced antiviral genes; sterol
regulatory element binding protein 2 (SREBP2), which
controls the expression of genes involved in cholesterol
biosynthesis7; and several stress-induced transcriptional
692 | o CToBER 2009 | VoLuME 9
www.nature.com/reviews/immunol
2009 Macmillan Publishers Limited. All rights reserved
REVIEWS
Box 1 | Module-specific transcriptional regulation of inflammatory gene expression
Adipose tissue
A type of connective tissue
that is specialized for the
storage of neutral lipids.
Transcription factor
A specialized nuclear protein
that can bind to DNA and
regulate gene expression. Most
transcription factors have
transactivation or repressor
domains but, in addition, they
can function as architectural
proteins and promote
chromatin remodelling by
recruiting additional activator
or repressor complexes.
Chromatin
Chromation is composed of
DNA together with histones
and other associated proteins.
Transcriptional co-regulator
Transcriptional co-regulators
lack DNA-binding specificity
and must be recruited to
their target genes through
interactions with transcription
factors or by binding to
particular chromatin
modifications. Co-regulators
have an important role in
modulating gene expression
and in many cases couple
transcription factors to
downstream effector
mechanisms for gene
regulation.
Many of the mechanisms that control gene expression operate in a gene-specific manner, which indicates that they
might control specific modules of the inflammatory response. Although module-specific regulatory mechanisms have
not yet been explored in detail, we describe a couple of examples to illustrate the biological contexts in which
module-specific control has an obvious advantage.
Lipopolysaccharide (LPS) tolerance is a state of hyporesponsiveness to LPS (and other inflammatory stimuli) that is
induced during conditions of excessive inflammation (such as sepsis) to limit inflammation-associated pathology.
LPS-tolerant cells are refractory to the induction of expression of inflammatory cytokines such as tumour necrosis factor
and interleukin-6 (IL-6), and this is due, at least in part, to the downregulation of expression of many inflammatory
signalling proteins80. Importantly, however, LPS-induced signalling in LPS-tolerant cells can still induce the expression of
genes that encode anti-inflammatory cytokines and antimicrobial peptides. The differential inducibility of these classes
of genes (or modules) is associated with distinct patterns of chromatin remodelling8183. This indicates that the
transcriptional regulation of LPS tolerance enables the inhibition of some functional programmes (for example, those
encoding inflammatory cytokines) while inducing other programmes (for example, antimicrobial effector functions),
which could be advantageous when a host has to deal with a persistent infection82.
As another example of module-specific transcriptional
regulation, we consider the multiple functions of different
LPS
Inflammatory cytokines
tissue-resident macrophage populations. All macrophages
are key orchestrators of the inflammatory response,
Chemotactic factors
but they also have tissue-specific functions that are
and receptors
TLR4
programmed by local factors (see figure). For example,
Coagulation factors
IL-10 induces colonic epithelium macrophages to carry out
immunomodulatory functions that are appropriate at this
Antimicrobial effector
functions
hostcommensal interface, whereas white adipose tissue
macrophages seem to have a role in metabolic regulation
Pathogen recognition
that is also tightly linked to the control of inflammation.
and phagocytosis
These tissue-specific functional programmes are
Antigen processing
transcriptionally regulated and are conferred by the
and presentation
expression of transcription factors that are unique to these
macrophage populations inhibitor of nuclear factor-B
Tissue repair factors
NS (IBNS) and peroxisome proliferator-activated
Metabolic regulators
receptor- (PPAR) in macrophages of the colonic
epithelium and white adipose tissue, respectively57,84.
regulators (such as N-ethylmaleimide-sensitive factor 2

for cellular stress induced by reactive oxygen species8,
hypoxia-inducible factor 1 for the hypoxic response9,
X-box-binding protein 1 for the unfolded protein
response 10 and aryl hydrocarbon receptor for the
xenobiotic-induced response11). In each case, the genes
that comprise a given transcriptional module are functionally related, which explains the requirement for their
coordinated control by dedicated transcriptional regulators. Importantly, the full repertoire of TLR-induced
transcriptional modules is currently unknown, as are
the transcriptional master regulators of these modules.
Nevertheless, the concept of transcriptional modules is
useful when considering the heterogeneity of a complex
transcriptional response, such as that induced by LPS
in macrophages.
Here, we first review what is known regarding
the regulation of the LPS-induced transcriptional
response by transcription factors, chromatin modifications and transcriptional co-regulators in macrophages,
and the relative roles of each of these components in
the inflammatory response. Then, we describe the
mechanisms by which various signalling pathways
modulate this transcriptional programme in distinct
biological contexts. Finally, we emphasize the modular
nature of the transcriptional control of inflammation
as being central to its physiological regulation and
therapeutic manipulation.
Nature Reviews | Immunology
Transcription factors
Induction of the LPS-dependent transcriptional response
in macrophages is orchestrated by many transcription
factors, consistent with the complexity of the response.
These transcription factors can be divided into three
categories on the basis of their mode of activation and
function. This classification is not intended to demarcate
mutually exclusive groups of transcription factors, but to
illustrate general principles regarding their mechanisms
of action and their role in the control of various inducible transcriptional modules in macrophages.
The first category (class I) consists of transcription
factors that are constitutively expressed by many cell
types and that are activated by signal-dependent posttranslational modifications. In most cases, these transcription factors are retained in the cytoplasm in the basal
state and their signal-dependent activation involves their
nuclear translocation. This class is the best characterized of the three categories of transcription factors and it
includes proteins that are known to have important roles
in inflammation, such as NF-B, IFN-regulatory factors
(IRFs) and cAMP-responsive-element-binding protein 1
(CREB1). The genes that are induced most rapidly by LPS
stimulation (the so called primary response genes) are
regulated by these transcription factors (FIG. 1).
There are multiple mechanisms that quickly terminate
the activation of NF-B and IRFs; for example, inhibitor of NF-B- (IB) exports NF-B from the nucleus
NATuRE REVIEwS | Immunology
VoLuME 9 | o CToBER 2009 | 693

REVIEWS
LPS
TLR4
ATF3
IRF
NF-B
Class I transcription factors
Secondary
response
genes
Class II
transcription
factors
Primary
response
genes
0.52 hours
Cytoplasm
C/EBP
PU.1
C/EBP
RUNX1
IRF8
Nucleus
Class III transcription

factors
Macrophagespecific gene
expression
Chromatin
remodelling
28 hours
Figure 1 | lipopolysaccharide (lPS)-induced primary and secondary response genes are regulated by three
categories of transcription factors. The first category (class I) consists of transcription factors that are activated
post-translationally by Toll-like receptor (TLR) signalling, often at the step of nuclear translocation.
Examples
include
Nature Reviews
| Immunology
nuclear factor-B (NF-B) and interferon-regulatory factor (IRF) proteins. These transcription factors control the
induction of the primary response genes. The second category (class II) is comprised of transcription factors that are
induced during the primary response, such as CCAAT/enhancer-binding protein- (C/EBP), which control induction of
the secondary response genes. A third category of transcription factors (class III), which includes PU.1, C/EBP,
runt-related transcription factor 1 (RUNX1) and IRF8, is not directly targeted by pro-inflammatory signals but is induced
during macrophage differentiation, and has a key role in specifying macrophage-specific patterns of inducible gene
expression. ATF3, activating transcription factor 3.
and/or facilitates its removal from the promoters of target

genes12,13. However, positive feed-forward mechanisms
might ensure the sustained activation of these transcription factors and their participation in subsequent waves
of gene induction; for example, the production of tumour
necrosis factor (TNF) triggered by LPS stimulation seems
to be crucial for autocrine signalling and induction of a
second wave of NF-B activation14,15.
The second category of transcription factors (class II)
are synthesized de novo after LPS stimulation. It is estimated that approximately 50 proteins make up this
group, many of which have poorly defined functions in
the context of the LPS-induced transcriptional response.
These transcription factors regulate subsequent waves of
gene expression after the primary response genes, and
they can do so over a prolonged period of time5. The
activity of these transcription factors is often subject to
positive feedback control, and because these proteins are
transcriptionally upregulated, a general principle here
seems to be transcriptional autoregulation. For example, the amplification of the LPS-induced transcriptional response by CCAAT/enhancer-binding protein-
(C/EBP) requires its autoinduction16. The stable upregulation of expression of these transcription factors could
also enable the reprogramming of macrophage functions. For this reason, we speculate that some transcription factors in this category might function as master
regulators of distinct functional modules.
The third category of transcription factors (class III)
consists of lineage-specific transcriptional regulators,
the expression of which is turned on during macrophage differentiation. Notable members of this group
include Pu.1 (also known as SPI1) and C/EBP, as well

as runt-related transcription factor 1 (RuNX1) and
IRF8 (REFS 17,18). Although none of these transcription factors is exclusive to macrophages (for example,
Pu.1 is also expressed by B cells), they are induced during macrophage differentiation and their combinatorial expression specifies the macrophage phenotype.
These proteins turn on constitutively expressed genes
in macrophages, remodel chromatin at inducible genes
and silence genes that are associated with alternative cell
fates. In mature macrophages, these transcription factors mediate cell type-specific responses to inflammatory signals and other stimuli, presumably by conferring
a permissive chromatin state on macrophage-specific
inducible genes. A unique mode of action of at least
some of the transcription factors in this category is the
organization of cell type-specific, higher order chromatin structure or chromosomal domains. In particular,
RuNX1 has been shown to anchor specific genomic
loci to the nuclear matrix (the architectural scaffold of
the nucleus) to assemble domains of active or inactive
chromatin19 that could determine the macrophagespecific patterns of active, silenced and inducible genes
on a global scale.
The transcription factors of the three categories mentioned above do not act independently, but function
coordinately to control the LPS-induced transcriptional
response. using a systems biology approach, Aderem and
colleagues have identified some of the regulatory circuits
that are shedding light on the logic of this combinatorial
control4,16,20. They have found, using global kinetic profiling, that LPS-induced gene expression in macrophages
REVIEWS
Table 1 | Three main classes of transcription factors regulate the lipopolysaccharide-induced transcriptional programme
Class of
transcription
factor
Transcription
factor activation
Intracellular localization Function of transcription factors

of transcription factors
mode of action
Examples
Class I:
constitutively
expressed but
latent
Signal-dependent
post-translational
modifications
Often regulated at
the point of nuclear
translocation
Responsible for the primary phase of

gene induction; there are multiple
mechanisms for rapidly terminating
signal-dependent transcription
factor activation
Integrate signals from

diverse signalling
pathways
NF-B, IRF3
Class II:
synthesized
de novo
Signal-dependent
transcriptional
induction
Most are constitutively

nuclear
Regulate subsequent waves of

gene expression; might stably
reprogramme gene expression
Some might specify

transcriptional modules
that encode functional
programmes in
macrophages
C/EBP
Class III:
induced
during cell
differentiation
Constitutively
expressed and
active
Constitutively nuclear
Regulate constitutive, as well as

inducible, gene expression; establish
macrophage-specific patterns of
chromatin remodelling during cell
differentiation
Might organize
higher-order
chromatin structure or
chromosomal domains
RUNX1,
PU.1,
C/EBP
C/EBP, CCAAT/enhancer-binding protein; IRF3, interferon-regulatory factor 3; NF-B, nuclear factor-B; RUNX1, runt-related transcription factor 1.
can be divided into a limited number of distinct patterns

of gene induction (and repression). using this approach,
combined with motif scanning of the promoters of these
genes in silico, they can define sets of genes that seem to
be coordinately regulated and the transcription factors
that are likely to control their expression. In this way, they
showed that the sustained expression of several inflammatory genes is mediated by a transcriptional network
that consists of three transcription factors: NF-B, which
functions as the activator; activating transcription factor 3
(ATF3), which functions as the inducible repressor; and
C/EBP, which functions as the inducible activator
and amplifier16. These observations also illustrate how
combinatorial control by multiple transcription factors
enables NF-B, which is required for the induction of most
of the LPS-induced genes, to engage in module-specific
regulation of inflammatory gene expression.
In addition, the temporal characteristics of transcription factor activation (and attenuation) might be
essential for determining the repertoire and specificity
of a complex transcriptional response. A series of elegant studies by Hoffmann and colleagues have shown
that perturbations in the dynamics of NF-B activation can result in profound, qualitative changes in gene
expression15,21. This is associated not only with stimulusintrinsic alterations in inducible gene expression,
but also results in the modification of transcriptional
responses triggered by other signalling pathways that
activate NF-B22,23.
So, the complex transcriptional programme induced
in macrophages after LPS stimulation is a product of the
coordinated action of the three categories of transcription factors described above (TABLE 1).
Dynamic chromatin remodelling

Recent studies have highlighted an important role for
chromatin in the control of inflammatory gene expression24. DNA methylation and RNA interference are other
epigenetic mechanisms for regulating gene expression,
and future studies will shed light on the functional
interplay between these processes in the control of

inflammation. Here, we discuss the role of chromatin
modifications in regulating inflammatory gene expression, with a focus on covalent histone modifications
(BOX 2). we describe what is known about how differential histone modifications can mediate gene-specific
transcriptional regulation and discuss how chromatin
architecture delimits cell type and signal specificity in
the transcriptional control of inflammation.
Histone modifications. Several histone modifications
have been shown recently to differentially regulate
subsets of LPS-induced genes and they are of particular interest because of their role in regulating specific
transcriptional modules within the multicomponent
transcriptional response mediated by LPS-induced
signalling (BOX 2) . one of the first studies in this
area indicated that phosphorylation of histone 3 at
serine 10 (H3S10) might have a gene-specific role in
NF-B recruitment 25. After LPS stimulation, the genes
encoding IL-6, IL-12p40 and CC-chemokine ligand
2 (CCL2), but not TNF and CCL3, undergo H3S10
phosphorylation at their promoters. This phosphorylation event depends on the mitogen-activated
protein kinase p38, and specific blockade of p38
activation inhibits H3S10 phosphorylation, NF-B
recruitment and gene induction25. It is unclear how
the phosphorylation of H3S10 is coupled to NF-B
recruitment, but this model is consistent with other
studies showing that H3S10 phosphorylation is associated with transcriptional activity 26. Moreover, the
inhibition of inflammatory gene induction by some
pathogens is associated with disruption of H3S10
phosphorylation (see below).
It is not known whether H3S10 is a direct substrate
of p38, but the data indicate that p38 or a p38-regulated
kinase, such as mitogen- and stress-activated kinase 1
(MSK1) or MSK2, might be recruited to a subset of
genes to confer H3S10-dependent transcriptional regulation. IB kinase- (IKK) can also be recruited to gene

REVIEWS
Box 2 | Covalent histone modifications and the control of gene expression
Histones, the proteins that package the genetic material, are subject to a large number of covalent modifications,
including lysine and arginine methylation, lysine acetylation, serine phosphorylation and lysine ubiquitylation85. The
counteracting activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs) establish the levels of
histone acetylation, whereas lysine methylation is regulated by SET (suppressor of variegationenhancer of
zestetrithorax) domain family proteins (for methylation) and lysine-specific demethylase 1 (LSD1) and Jumonji C (JMJC)
domain-containing proteins (for demethylation)85. Strahl and Allis first proposed that histone modifications are found in
non-random patterns in the genome to form a histone code, with distinct combinations of modifications specifying
unique states of gene expression86. Reader proteins bind to and specifically discriminate between different histone
modifications, and have a crucial role in coupling the recognition of histone modifications to the downstream effector
mechanisms that regulate gene expression; they can recruit other chromatin-modifying factors or the transcriptional
machineries that control the initiation and elongation phases of transcription and mRNA processing86.
In the past few years, genome-wide maps of histone modifications coupled with transcriptional profiling have
identified many histone modifications as being either active or inactive. Histone 3 lysine 4 (H3K4) trimethylation, for
example, is associated with transcriptionally active or poised loci, whereas H3K27 and/or H3K9 trimethylation correlate
with gene silencing85. Moreover, whereas some histone modifications seem to associate strongly with a particular state
of gene expression (for example, active, poised or silent loci), others seem to mark much smaller subsets of active or
inactive genes. Histone modifications that associate strongly with a particular state of gene expression probably
regulate general features of gene induction or repression, often because they couple directly to various transcriptional
machineries. For example, transcription factor IID (TFIID), which is essential for promoter recognition by RNA
polymerase II, is recruited to inducible genes in part through promoter-localized H3K4 trimethylation87. This provides
the rationale for the nearly invariant distribution of H3K4 trimethylation at the promoters of transcriptionally active
and poised genes. Conversely, modifications such as H3K27 trimethylation and H2AK119 ubiquitylation might function
more exclusively to control only subsets of inducible or repressible genes, and therefore might regulate transcriptional
modules within a more complex transcriptional response.
Small interfering RNA

(siRNA)-mediated
knockdown
Double-stranded RNAs
(dsRNAs) with sequences that
precisely match a given gene
can knockdown the
expression of that gene by
directing RNA-degrading
enzymes to destroy the
encoded mRNA transcript. The
two most common forms of
dsRNA used for gene silencing
are short usually 21-base
pair long siRNAs or the
plasmid-delivered short hairpin
RNAs (shRNAs).
Polycomb proteins
A group of proteins that are
required to maintain the
silencing of genes encoding key
developmental regulators, such
as Hox.
promoters in a signal-dependent manner to phosphorylate H3S10 (REFS 27,28). These examples illustrate that
chromatin can be a direct, albeit distal, target of signal
transduction cascades, and they underscore the fundamental role of chromatin in regulating geneenvironment interactions; however, it is not known what directs
the promoter-specific targeting of these kinases.
Perhaps even more interesting are the inhibitory
histone modifications that mark subsets of inducible
genes. ubiquitylation of H2A at lysine 119 (H2AK119)
is one such modification that inhibits the basal expression level of some LPS-inducible genes for example, CCL5, CXC-chemokine ligand 10 (CXCL10) and
CXCL2, but not CXCL1 in a macrophage cell line29.
This study proposed that ubiquitylation of H2AK119
at these gene promoters is necessary to prevent recruitment of the elongation factor FACT (facilitates chromatin transcription) complex. LPS-induced signalling
triggers the gene-specific recruitment of the deubiquitylating enzyme 2A-HuB (also known as DZIP3),
the activity of which is necessary for H2AK119
deubiquitylation and hence gene induction29. Consistent
with this model, small interfering RNA (siRNA)-mediated
knockdown of 2A-HuB is sufficient to decrease the
level of basal H2AK119 ubiquitylation and leads to
the recruitment of FACT to gene promoters and small
but significant increases in the level of basal gene
expression29. This indicates that at these promoters,
H2AK119 ubiquitylation might be necessary to prevent low-level, leaky gene expression. It is interesting
that some, but not all, inflammatory genes seem to
require this additional regulatory mechanism for
maintaining basal repression; perhaps these genes
encode proteins with biological functions that must
be particularly tightly regulated.
Another subset of LPS-inducible genes undergoes

signal-dependent demethylation of trimethylated
H3K27 as a prerequisite for induction. The enzyme
responsible for this activity, lysine-specific demethylase 6B (KDM6B; also known as JMJD3), is itself
transcriptionally upregulated after LPS stimulation,
and siRNA-mediated knockdown of KDM6B inhibits
demethylation and the induction of Bmp2 (bone morphogenetic protein 2) expression30. This is consistent
with previous studies that have established a role for
H3K27 trimethylation in maintaining gene silencing through the recruitment of Polycomb proteins. As
removal of the H3K27 inhibitory modification enables gene expression during cellular differentiation31,
KDM6B-dependent regulation of an LPS-inducible
gene30 indicates that macrophage activation has some
features that are similar to differentiation.
It is important to point out that repressive histone modifications, such as H2AK119 ubiquitylation
and H3K27 trimethylation, are additional regulatory
checkpoints of inducible gene expression. Stimulusdependent induction of genes bearing these modifications requires recruitment of the appropriate
chromatin-modifying enzymes; hence, these histone
modifications restrict both the types of biological signal and the classes of genes that are induced.
Moreover, these repressive histone modifications
could be targeted by anti-inflammatory signalling
pathways as a means to enforce gene-specific inhibition of the inflammatory response (see below). It
should be interesting to characterize further the LPSinduced transcriptional response with respect to other
inhibitory epigenetic modifications, including H3
arginine 2 dimethylation, H3K9 dimethylation and
DNA methylation.
REVIEWS
a CpG island-associated primary response gene
Basal transcription
Methylation
Acetylation
H3K4
P Ser5
H3K9
Nucleosome
H4
Stimulus-dependent
transcription
Unspliced
transcript
SP1
Acetylation
H4
HAT
HAT
P-TEFb
NF-B
Pol II
Spliced
transcript
Ser5
P Ser2
Pol II
b Secondary response gene

Inaccessible chromatin
Remodelling
Methylation
Acetylation
HAT
BRG1
NF-B
IRF3
H3K4
H3K9
Ser5
Acetylation
H4
HAT P-TEFb
NF-B
P Ser2
BRG1
IRF3
Pol II
Figure 2 | Two distinct modes for regulating inducible genes. a | At primary response genes that have
promoters containing CpG islands, Toll-like receptor (TLR) signalling induces a switch from basal gene transcription
(mediated by serine 5 (Ser5)-phosphorylated RNA polymerase II (Pol II)) to the stimulus-dependent
production
of
Nature Reviews
| Immunology
mature, processed transcripts, which depends on the recruitment of positive transcription elongation factor b
(P-TEFb). b | By contrast, secondary response genes require chromatin remodelling as a prerequisite for transcription
factor binding and the recruitment of histone-modifying enzymes and the general transcription initiation machinery.
BRG1, BRM/SWI2-related gene 1 (also known as SMARCA4); HAT, histone acetyltransferase; IRF3, interferon-regulatory
factor 3; NF-B, nuclear factor-B; SP1, specificity protein 1.
Nucleosome
This is the basic repeating unit
of eukaryotic genomes.
Nucleosomes consist of 146
base pairs of DNA wound
around an octamer of histone
proteins.
SWISNF
(switching-defective
sucrose non-fermenting). An
ATP-dependent chromatin
remodelling protein complex
that was first identified in
yeast. Related complexes exist
in mammals (where they are
known as BAF) and are
involved in the chromatin
remodelling of various genes.
CpG island
A sequence of 0.52
kilobases that is rich in CpG
dinucleotides. They are
mostly located upstream of
housekeeping genes and also
of some tissue-specific genes,
and they coincide with gene
promoters in these contexts. In
mammalian cells, most CpG
islands are hypomethylated
with respect to the rest of the
genome.
Chromatin architecture. Chromatin remodelling 32 can

also regulate the dynamic induction of inflammatory
gene expression. This activity is mediated by chromatin remodelling complexes, which use ATP to slide
nucleosomes relative to DNA or to alter nucleosome
DNA contacts, thereby modulating the accessibility of
chromatin-associated DNA to transcriptional regulators33. Chromatin remodelling complexes are generally
thought to be regulated mainly at the level of recruitment to target gene promoters. However, a recent
study showed that the chromatin remodelling complex
SWISNF (switching-defectivesucrose non-fermenting;
also known as BAF) can also be regulated after recruitment to a target gene by a Ca2+calmodulin-dependent
signal in LPS-stimulated macrophages34.
Smale and colleagues35 have recently shown that the
requirements for chromatin remodelling differ between
LPS-inducible primary and secondary response genes
(FIG. 2) . The induction of secondary response genes
requires de novo protein synthesis, whereas the upregulation of expression of primary response genes does
not (although this does not preclude the regulation of
primary response genes in the secondary phase of the
transcriptional response)35. Chromatin remodelling
by SwISNF is necessary for the induction of secondary response genes (and the delayed primary response
genes), but not for the early primary response genes35.
Indeed, subsequent studies showed that whereas the
promoters of secondary response genes undergo LPSdependent H3K4 trimethylation and H3 acetylation, the
promoters of SwISNF-independent primary response
genes have high basal levels of these active histone modifications, even before LPS stimulation32,36,37. Importantly,
the presence of active chromatin correlates closely with
promoter GC content, which indicates that the underlying DNA sequence at promoters with CpG islands, which
are found in many SwISNF-independent primary
response genes, could direct chromatin remodelling to
the active state37. This is supported by the observations
that these CpG islands are associated with low nucleosome density and do not assemble stable nucleosomes
in vitro 37, and that these promoters also bear active
chromatin even in embryonic stem cells32,37, which indicates that chromatin remodelling is not a consequence
of cellular differentiation. Previous studies 38,39 have
indicated a role for chromatin in restricting the accessibility of transcription factors to their target genes,
and these studies expand on this concept, showing
that active chromatin might enable more promiscuous
induction of GC-rich promoters of primary response
genes, whereas inactive chromatin at the promoters of
secondary response genes restricts gene induction to
a limited range of stimuli in specialized cell types32,37.
Along these lines, it is noteworthy that GC-rich primary
response genes, but not most secondary response genes,
are regulated by the transcriptional co-repressors nuclear
receptor co-repressor (NCoR) and REST co-repressor
(RCoR; also known as CoREST)32 (see below), perhaps
to counter the active chromatin that is associated with
these genes in the basal state. It will be interesting to
further characterize primary and secondary response
genes with respect to other features of chromatin, and
to understand the consequences of these chromatin
modifications for gene induction.
Further analyses of the GC-rich primary response
genes have uncovered additional surprises (FIG. 2) .
In the basal state, these genes (but not secondary
response genes) are transcribed at low levels by RNA

REVIEWS
Transcriptional co-repressor
Transcriptional co-repressors
are protein complexes,
including NCOR and SMRT,
that associate with nuclear
hormone receptors and other
transcriptional regulators to
inhibit gene transcription.
A common mechanism of
repression is by recruiting
histone-deacetylase complexes
to reverse the actions of
histone acetyltransferases.
CBPp300
CREB-binding protein (CBP)
and p300 are transcriptional
co-activators that interact with
many transcription factors to
promote recruitment of the
RNA polymerase holoenzyme
and other transcriptional
regulators, thereby allowing
transcriptional induction. In
addition, p300 and CBP have
histone acetyltransferase
activity, such that these
proteins can influence
chromatin activity by
modulating nucleosomal
histones.
Histone acetyltransferase
A protein that acetylates core
histones on lysine residues,
which has important regulatory
effects on chromatin structure
and assembly, and on gene
transcription. In general,
increased levels of histone
acetylation are associated with
activation of gene expression.
polymerase II (Pol II) that is phosphorylated on

serine 5 (Ser5P) but not on Ser2 of its carboxy terminal domain. Consistent with a crucial role of Ser2P in
recruiting the RNA processing and splicing machinery,
these basal transcripts of the primary response genes are
extensively elongated but are not spliced32. LPS-induced
signalling recruits positive transcription elongation
factor b (P-TEFb), which phosphorylates Pol II on Ser2
and results in the generation of high levels of mature,
spliced transcripts of the primary response genes. So,
an important checkpoint for inducible gene expression seems to involve signal-dependent engagement of
P-TEFb, conversion of Ser5P Pol II to the Ser2P form,
and the production of mature, spliced transcripts of
primary response genes32 (BOX 3).
The organization of inducible transcriptional
responses into a primary and a secondary component
was first described for the mitogen-induced response40,
and it is probably generally applicable to all other inducible stimuli. It will be interesting to see whether the different mechanisms described here for the regulation of
CpG-associated primary response genes and secondary
response genes will also apply to other inducible gene
expression programmes.
Co-regulators of the inflammatory response

Co-regulators are transcriptional regulators that, unlike
transcription factors, lack DNA-binding specificity and
must be recruited to their target genes through other
mechanisms. Because many co-activators and corepressors (co-regulators that activate and inhibit gene
expression, respectively) function in the LPS-induced
transcriptional response, here we focus on only a few of
the most important or interesting examples.
Co-activators. Inflammatory gene induction by transcription factors such as NF-B depends on co-activator
proteins. These transcriptional regulators can promote
inflammatory gene expression in multiple ways. Many
co-activators have histone-modifying activities and

can remodel chromatin at target genes to promote
gene induction. For example, CBPp300-mediated histone acetylation can be coupled to the recruitment of
SwISNF and other factors41, whereas PCAF (p300
CBP-associated factor) and GCN5 (general control of
amino-acid synthesis 5) histone acetyltransferases can
direct transcription elongation factors to target genes32.
other co-activators lack intrinsic enzymatic activity
and might promote the assembly of a transactivating
complex. Yet another example of a co-activator function
is provided by the IB family member IB. This protein is transcriptionally induced by TLR signalling and
promotes the exchange of inhibitory p50 (also known
as NF-B1) homodimers for transcriptionally active
p50p65 (also known as RELA) heterodimers on some
target gene promoters42.
Intriguingly, recent studies indicate that p65 and
IRF3 have additional roles in the LPS-induced transcriptional programme as co-activators as well as DNAbinding transcription factors. Leung et al. showed that
IRF3-dependent regulation of Ccl2 expression requires
IRF3 functioning as a co-activator for p65 (REF. 43) .
Consistent with this finding, Glass and colleagues
showed that the glucocorticoid receptor inhibits a
subset of LPS-inducible genes by blocking the coactivator function of IRF3. In addition, p65 and IRF3
were shown to interact, and the glucocorticoid receptor
could disrupt this binding 44. Conversely, p65 was
suggested to be a co-activator for IRF3 and to facilitate
IRF3 binding to DNA45.
why do some but not all p65-regulated genes engage
IRF3 as a co-activator? It is possible that subtle differences in the NF-B-binding site in a gene can induce
conformational changes in p65 in an allosteric manner, thereby conferring specificity of co-activator binding 43,46. p65 and IRF3 might have evolved mutually
co-activating functions because of their parallel roles
in many aspects of the inflammatory response, and the
Box 3 | Transcription initiation and elongation

In the classical model of transcription initiation, the key regulated step is the signal-dependent engagement of RNA
polymerase II (Pol II) at inducible promoters. Transcription factors that are activated by a triggering signal are recruited to
target promoters, where they have an essential role in directing the recruitment of the transcription initiation machinery.
However, it has also been appreciated for some time that at heat shock-inducible promoters in Drosophila melanogaster,
Pol II is constitutively bound but stalled88. The essential elongation factor positive transcription elongation factor b
(P-TEFb) is recruited following heat shock, and its kinase activity is necessary to inactivate inhibitors of elongation and
to activate positive regulators, thereby triggering productive transcription elongation. In addition, the carboxy terminal
domain of Pol II contains heptapeptide repeats that are also important targets of P-TEFb; when phosphorylated at
serine 2 (Ser2) in the heptapeptide repeats, the carboxy terminal domain of Pol II can function as a platform for the
recruitment of various mRNA-processing machineries. So, at heat shock-inducible promoters of D. melanogaster,
signal-dependent gene induction seems to be regulated at the level of P-TEFb-mediated transcription elongation88.
Interestingly, recent studies have indicated that this phenomenon might be much more prevalent than originally
thought. In several studies, Pol II was shown to bind many promoters across the genome in the absence of active gene
induction. This led to the proposal that many genes are actually associated with promoter-bound, transcriptionally
stalled Pol II in the basal state, and that signal-dependent recruitment of P-TEFb is the key regulatory checkpoint8991.
Interestingly, however, a recent study showed that signal-independent binding of Pol II to promoters in the basal state
is associated with basal transcription that produces full-length but unspliced transcripts32. This indicates that Pol II
binding in some other contexts could also be associated with basal transcription. It will be important to determine
whether signal-independent Pol II recruitment is associated with a block of elongation versus basal transcription in
a cell type-specific or gene-specific manner.
REVIEWS
Histone deacetylase
A protein that removes the
acetyl groups from lysine
residues that are located at the
amino termini of histones. In
general, decreased levels of
histone acetylation are
associated with the repression
of gene expression. The
balance of histone acetylation
is maintained by the interplay
between histone deacetylases
and histone acetyltransferases.
combined transactivation potential of the two factors

could result in increased inducible transcription of target genes. It would be interesting to determine if p65
and IRF3 can co-activate other transcription factors in
the regulation of additional functional programmes.
Co-repressors. NCoR and the closely related protein
SMRT (silencing mediator of retinoid and thyroid
receptors) have emerged as important regulators of
inflammatory gene expression. The NCoR and SMRT
multiprotein co-repressor complexes contain histone
deacetylases (HDACs) and potentially other activities
for inhibiting gene expression, and their stimulusdependent dismissal from the promoters of inflammatory genes (a phenomenon known as derepression)
is a prerequisite for the inducible expression of these
genes. NCoR is directed to many inflammatory genes,
in part by the transcription factor JuN (also known as
AP1), and its clearance is triggered by signal-induced
exchange of JuN homodimers for transcriptionally
active JuNFoS heterodimers47,48. By contrast, SMRT
is recruited to gene promoters by the transcriptional
repressor TEL (translocationETSleukaemia) 47 .
Interestingly, some inflammatory genes are regulated
by both NCoR and SMRT co-repressor complexes,
Basal state
Methylation
H3K4
H3K9
HDAC
H4
Co-repressor
Acetylation
Pol II
Repression of
LPS-inducible
inflammatory genes
Inactive transcription
factor complex
PPAR
LXRs
Others
TLR ligands or other

pro-inflammatory signals
Ser5
HAT
Transcript
P Ser2
Co-activator
Pol II
Activation of
LPS-inducible
inflammatory genes
Active transcription
factor complex
Figure 3 | Control of inflammatory gene expression by co-activators and

co-repressors. In the basal state, co-repressors such as nuclear receptor co-repressor
| Immunology
(NCOR), silencing mediator of retinoid and thyroid receptorsNature
(SMRT)Reviews
and REST
co-repressor (RCOR) are recruited to target promoters by various transcription factors,
where they counter inflammatory gene expression by inhibiting histone acetylation (and
possibly also other activating histone modifications such as H3K4 trimethylation).
Toll-like receptor (TLR) signalling and other pro-inflammatory signals induce the
exchange of co-repressors for co-activators on target promoters, resulting in the
activation of gene expression. Nuclear receptors such as peroxisome proliferatoractivated receptor- (PPAR), glucocorticoid receptor and liver X receptors (LXRs)
constitute an important class of anti-inflammatory regulators, which block inflammation
in part by inhibiting this exchange. In the best studied case of NCOR, inflammatory signals
trigger its proteasomal degradation, and this can in turn be inhibited by PPAR and LXRs.
HAT, histone acetyltransferase; HDAC, histone deacetylase; Pol II, RNA polymerase II.
indicating that this group of genes can be regulated

by a greater diversity of signals47,49. In this regard, it is
interesting that another co-repressor complex, RCoR,
is also associated with inflammatory genes and is
cleared from target promoters after LPS-induced signalling 32, which indicates that it might also provide a
stimulus-specific regulatory checkpoint. Importantly,
whereas LPS stimulation dismisses NCoR from target
genes before their induction, a counteracting activity is
provided by nuclear receptor-mediated stabilization of
NCoR (FIG. 3 and see below).
with respect to the control of inflammatory gene
expression by these co-repressors, several interesting
questions remain. what is the repertoire of genes that are
regulated by each co-repressor? why are some genes controlled by more than one co-repressor? How do these corepressors mediate repression, and do they have distinct
modes of repression? How are they recruited in the basal
state and dismissed in a signal-dependent manner?
Negative regulation of inflammatory genes

The induction of an inflammatory response is essential
for host defence during infection, but timely resolution is also important to limit the detrimental effects
of inflammation, particularly when it is inappropriately
sustained or increased. For this reason, acute inflammation leads to the upregulation of expression of many
negative regulators of inflammation. These negative
regulators fall into two main categories: signal-specific
regulators and gene-specific regulators. The first category consists of regulators that inhibit signal transduction by TLRs and other inflammatory pathways,
and includes A20, ST2, IL-1R-associated kinase M
(IRAKM) and suppressor of cytokine signalling (SoCS)
proteins50. Although these proteins inhibit inflammatory signalling through various mechanisms, they all
function proximal to the receptor, and so are expected
to block gene induction by that receptor in a global
manner. The second category includes transcriptional
repressors or other negative regulators that function to
modulate gene expression.
There are two types of transcriptional negative regulator: basal repressors and inducible repressors. Basal
repressors are constitutively expressed and are important for the basal repression of many inflammatory
genes. For example, homodimers of the NF-B family
member p50 can function as transcriptional repressors that are exchanged for transcriptionally active
p65p50 heterodimers as a result of signalling induced
by LPS51. JuN49, SIRT6 (silent mating type information
regulation 2 homologue 6)52 and co-repressors such as
NCoR47,49, SMRT47 and RCoR32 have also been shown
to mediate basal repression of a subset of LPS-inducible
inflammatory genes (FIG. 3) . By contrast, inducible
repressors are normally expressed only at low levels
or not at all, but are transcriptionally induced by LPSinduced signalling, indicating that they are part of a
negative feedback mechanism that limits the inflammatory response. Importantly, inducible repressors block
the expression of secondary response genes, whereas
basal repressors inhibit the expression of primary

REVIEWS
response genes associated with CpG islands. These
primary response genes might require repression in
the basal state to prevent low-level constitutive expression, whereas the inaccessible nature of the chromatin
at secondary response genes is generally refractory to
basal gene expression due, in part, to the occlusion of
binding sites for transcription factors. Therefore, it is
probable that different modes of transcriptional repression can operate to inhibit primary and secondary
response genes.
Endotoxic shock
A clinical condition that is
induced by hyper-reaction of
the innate immune system to
bacterial LPS. It is mediated by
the inflammatory cytokines
IL-1 and TNF, which are
produced in large amounts due
to sustained stimulation of
TLR4 by LPS.
Septic shock
A systemic response to severe
bacterial infections, which is
generally caused by
Gram-negative bacterial
endotoxins, that leads to a
hyperactive and out-of-balance
network of inflammatory
cytokines, affecting vascular
permeability, cardiac function
and metabolic balance. This
can lead to tissue necrosis,
multiple-organ failure and
death.
LPS-inducible negative feedback loops. Members of the

IB family are noteworthy examples of inducible negative
regulators. IB, which was the first identified member
of this family, mainly inhibits the expression of NF-Bdependent genes on a global level, but IBNS and B cell
lymphoma 3 (BCL-3) limit inflammation in a genespecific manner 5355. IBNS and BCL-3 are transcriptionally induced by LPS stimulation, and their genetic deletion
results in the enhanced induction of inflammatory genes
and increased susceptibility to endotoxic shock54,56. Both
proteins mediate the negative regulation of inflammation by modulating the exchange of active NF-B dimers
for their inactive counterparts at target gene promoters.
Interestingly, IBNS and BCL-3 seem to control distinct
sets of genes IL-6, IL-12p40 and IL-18 for IBNS, and
TNF, IL-10 and IL-1 for BCL-3 although the basis of
this specificity remains to be determined54,55.
ATF3 is another transcriptional negative regulator
that can be induced by LPS stimulation. Similarly to
IBNS and BCL-3, loss of ATF3 leads to hyperinduction of a subset of LPS-inducible genes and increased
susceptibility to endotoxic shock20. ATF3-mediated
transcriptional inhibition can be reversed by HDAC
inhibitors, which indicates that at least one key aspect
of the function of ATF3 is to recruit HDACs to target
genes20. Moreover, ATF3 is a member of the CREB family of basic leucine zipper transcription factors and has
been shown to form a regulatory circuit with NF-B and
C/EBP at some LPS-inducible genes16. The transcriptional programme induced by LPS is undoubtedly controlled by many other transcriptional repressors, the
identity and mechanisms of function of which remain
poorly characterized and warrant further study.
Finally, it is worth noting that many of the same
proteins that function in the LPS-induced negative
feedback loops are also upregulated by other pathways
that inhibit inflammatory gene expression. For example, IL-10, which is an important anti-inflammatory
cytokine for many cells of the immune system including macrophages, can also induce the expression of
both IBNS and BCL-3 (REFS 57,58). Interestingly, in
colonic macrophages, IL-10-mediated induction of
IBNS expression seems to be of particular importance
in inhibiting the production of IL-6 and other inflammatory responses57. This is shown by the development
of colitis in IBNS-deficient mice, similarly to IL-10deficient mice54. In other settings, however, BCL-3
or other IL-10-inducible negative regulators might
be more important for mediating IL-10-dependent
suppression of inflammation.
Negative regulation by anti-inflammatory pathways.

Inflammatory gene induction is subject to negative regulation by a large number of pathways and mechanisms
that are important to limit the pathophysiological consequences of excessive inflammation. These include antiinflammatory cytokines (such as IL-10 and transforming
growth factor- (TGF)), nuclear hormone receptors
(including, but not limited to, glucocorticoid receptors, liver
X receptors (LXRs), peroxisome proliferator-activated
receptors (PPARs) and vitamin D receptor) and cAMP.
Consistent with the crucial anti-inflammatory role
of IL-10, mice lacking this cytokine mount exaggerated
inflammatory responses to infection and in septic shock59
and develop spontaneous colitis due to perturbed host
commensal homeostasis in the intestines59. An important mechanism by which IL-10 inhibits inflammation
is at the level of transcription, as indicated by the ability of cycloheximide treatment to block IL-10-mediated
inhibition of primary response genes60. As mentioned
above, IL-10 induces the expression of several negative
regulators that mediate gene-specific repression of the
LPS-induced inflammatory response. IBNS and BCL-3
disrupt NF-B-mediated transcription, but the function of other IL-10-induced proteins and whether they
modify chromatin in a gene-specific manner are not
clear. cAMP is another negative regulator of inflammation61. It is activated by G-protein-coupled receptors for
glucagon, acetylcholine, adenosine and many other
biological signals. cAMP works mainly by activating
protein kinase A (PKA), but the exact mechanism
of cAMP-mediated inhibition of inflammatory gene
expression is not known.
Nuclear receptors are another major class of transcriptional negative regulators of inflammation. These include
glucocorticoid receptors, PPARs and LXRs. These proteins therefore integrate the control of inflammation with
various important physiological functions, such as metabolism62. Nuclear receptors are thought to inhibit inflammation by at least two distinct mechanisms. Activated
nuclear receptors can directly induce gene expression
programmes that are anti-inflammatory. For example, the
activation of glucocorticoid receptor increases the uptake
of apoptotic cells by macrophages concurrent with the
inhibition of inflammatory signalling63. Nuclear receptors
can also inhibit inflammation directly, in a gene-specific
manner. For example, PPAR activation results in disassociation of the BCL-6 co-repressor from the Ccl2 promoter,
thereby enabling recruitment of BCL-6 to inflammatory
target genes to mediate transcriptional inhibition 64.
Alternatively, activated nuclear receptors can be recruited
to some inflammatory genes where they inhibit the clearance of the co-repressors NCoR and SMRT, a process
known as transrepression62. Interestingly, transrepression
by LXRs and PPAR results in the impaired induction of
distinct subsets of inflammatory genes, but it is not known
what dictates the differential gene-specific recruitment of
LXRs and PPAR62. The multitude of mechanisms by
which nuclear receptors can inhibit inflammatory gene
expression underscores the importance of transcriptional control of inflammation by metabolism and other
physiological processes.
REVIEWS
SIRT proteins, which are nicotinamide adenine dinucleotide (NAD)-dependent deacetylases of the class III
HDAC family, have also been implicated recently in the
transcriptional control of inflammatory genes. unlike its
yeast homologue Sir2 and the class I and class II HDACs,
SIRT1 targets transcription factors and co-activators for
deacetylation; SIRT1 counters p300-mediated acetylation of NF-B p65 in its transactivation domain, which
leads to a block of p65-dependent gene induction that
is independent of DNA binding 65. SIRT6 also inhibits
NF-B activity, but in this context NF-B itself is not the
target; instead, SIRT6 deacetylates H3K9 at the promoters of some NF-B-regulated genes66. Acetylated H3K9
is closely associated with transcriptional activation
across the genome, and SIRT6-mediated deacetylation
of H3K9 represses both basal and stimulus-dependent
gene induction66. These studies raise the possibility that
SIRT1 and SIRT6 (and perhaps other members of the
family) might couple energy status (in the form of NAD
sensing) to the control of inflammation.
Finally, HES and HEY are two other LPS-inducible
transcriptional repressors that function to attenuate
the induction of a subset of inflammatory responses67.
In an intriguing example of signalling pathway crosstalk, LPS-dependent upregulation of expression of
HES and HEY by macrophages requires concomitant
activation of the Notch pathway and the downstream
transcriptional activator recombination-signal-binding
protein-J (RBP-J). Moreover, IFN signalling blocks
HES and HEY upregulation, illustrating a novel mechanism for the well-established priming effect of IFN on
LPS-stimulated macrophages67. Global transcriptional
profiling to define the repertoire of HES- and HEYrepressed genes should help to define the physiological
contexts in which Notch signalling inhibits inflammatory
gene expression.
Deacetylation
Acetylation is a
post-translational modification
of chromatin components,
particularly histones, and other
proteins. Histone deacetylases
have been identified as
components of nuclear
co-repressor complexes.
Notch pathway
A pathway comprising highly
conserved transmembrane
receptors that regulate cell-fate
choice in the development of
many cell lineages, and so are
crucial for the regulation of
embryonic differentiation and
development.
MicroRNAs
Single-stranded RNA
molecules of approximately
2123 nucleotides in length
that are thought to regulate the
expression of other genes.
Pathogen-mediated chromatin remodelling. Pathogens

can modulate inflammation at multiple levels. General
inflammatory signalling pathways are a common
target of pathogen virulence factors, but in addition, pathogens have evolved mechanisms to inhibit
inflammation in a module-specific manner. For
example, Mycobacterium tuberculosis subverts the
IFN response in macrophages without disrupting
the JAKSTAT (Janus kinasesignal transducer and
activator of transcription) pathway, and it does so in
a gene-specific manner that targets a subset of IFNregulated genes68. In addition, several recent studies
have highlighted how pathogens can modify chromatin at inflammatory genes69. Inhibition of TNF (but
not IL-10) production by infection with Toxoplasma
gondii is associated with decreased H3 acetylation and
H3S10 phosphorylation, and decreased recruitment of
p65 to the Tnf promoter 70. Interestingly, several other
pathogens also downregulate H3S10 phosphorylation,
presumably for the purpose of blocking expression
of a subset of inflammatory genes71. It is not known
why or how different pathogens have converged on
this particular chromatin modification to subvert the
host inflammatory response. p38 is a common target
of pathogen virulence factors, so it is possible that the

downregulation of H3S10 phosphorylation is a consequence of p38 inhibition. It will be interesting to see if
pathogens use other chromatin remodelling activities
to subvert specific functional programmes of the host
immune response.
Additional control mechanisms

Recent studies have provided evidence of a potential
role for long non-coding RNAs (lncRNAs) in regulating inflammatory gene expression 72,73. The role of
microRNAs in this process has been recently reviewed74
and will not be addressed here. Apart from their role
in X chromosome inactivation and imprinting, the
function of lncRNAs is not well understood. Broadly
speaking, lncRNAs have been described that direct
the expression of specific genomic loci (regulation in
trans); alternatively, the process rather than the product
of lncRNA transcription has been shown to inhibit or
activate gene expression (regulation in cis)75. An example of regulation in cis is the requirement for the signaldependent transcription of a lncRNA for the induction
of the closely juxtaposed lysozyme gene73. Lysozyme is
an antimicrobial enzyme that hydrolyses bacterial cell
wall peptidoglycan, the expression of which is induced
during macrophage differentiation. In the basal state,
the insulator protein CCCTC-binding factor (CTCF)
is bound to regulatory elements of the lysozyme gene,
but after LPS-induced signalling, transcription of a
lncRNA through this regulatory region of the lysozyme gene displaces CTCF and leads to local chromatin remodelling and induction of the lysozyme gene.
Insulator proteins can block the interactions between
regulatory regions of a gene76, so the displacement of
CTCF might enable the distal enhancer of the lysozyme
gene to interact, in a signal-dependent manner, with
the promoter 73. In light of this, a recent study identified ~1,600 highly conserved lncRNAs in mammalian
cells, of which more than 20 can be induced by LPS
stimulation of bone marrow-derived dendritic cells72.
Some of these inducible lncRNAs might regulate other
genes in cis, and it will be interesting to understand
what categories of LPS-inducible genes are subject to
this type of control.
Previous studies have shown that many proinflammatory cytokine and chemokine genes are also
regulated post-transcriptionally. These genes encode
mRNAs with Au-rich elements (AREs) in the 3 untranslated regions, which are recognized by a network of
ARE-binding proteins that control mRNA metabolism
by distinct mechanisms, including regulation of translation and mRNA decay. So, the maximal induction of
TNF, IL-1 and IL-6 by LPS requires inactivation of
ARE-mediated mRNA destabilization in a manner that
depends on the p38 mitogen-activated protein kinase
pathway 77,78. Finally, the endonuclease ZC3H12A was
recently shown to regulate the stability of inducible
gene transcripts79. In its absence, macrophages produce
increased levels of certain pro-inflammatory cytokines
such as IL-6 and IL-12, and mice that lack ZC3H12A
develop inflammation and severe immune diseases that

REVIEWS
lead to early death. ZC3H12A is thought to target a distinct repertoire of mRNAs, independently of ARE recognition, further underscoring the role of mRNA transcript
stability in regulating the inflammatory response.
Conclusions and future perspectives

The LPS-inducible transcriptional programme has
served as an excellent model for understanding the
transcriptional control of inflammation. Many questions remain that would be of interest to address. First,
we have focused on several pathways that negatively
regulate inflammation to illustrate some general principles. But these are only a small fraction of the total repertoire of physiological signals that inhibit inflammation,
underscoring the necessity of being able to fine-tune
inflammation in a module-specific manner. Future studies that address the mechanisms of inhibition by these
different signals will be important. For example, what
sets of genes and functional programmes are inhibited
by IL-10 compared with TGF? Are there transcriptional repressors that are shared by multiple negative
regulatory pathways? of the several repressors that are
activated or induced by a particular negative regulator
of inflammation, what are the relative contributions of
individual repressors and how do they differ in distinct
cell types and physiological settings? Pathways that positively modulate inflammation undoubtedly exist but are
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
Hotamisligil, G. S. Inflammation and metabolic

disorders. Nature 444, 860867 (2006).
Medzhitov, R. Origin and physiological roles of
inflammation. Nature 454, 428435 (2008).
Nathan, C. Points of control in inflammation.
Nature 420, 846852 (2002).
Ramsey, S. A. et al. Uncovering a macrophage
transcriptional program by integrating evidence
from motif scanning and expression dynamics.
PLoS Comput. Biol. 4, e1000021 (2008).
Ravasi, T., Wells, C. A. & Hume, D. A. Systems biology
of transcription control in macrophages. Bioessays
29, 12151226 (2007).
Ting, J. P., Kastner, D. L. & Hoffman, H. M.
CATERPILLERs, pyrin and hereditary immunological
disorders. Nature Rev. Immunol. 6, 183195 (2006).
Horton, J. D. & Shimomura, I. Sterol regulatory
element-binding proteins: activators of cholesterol
and fatty acid biosynthesis. Curr. Opin. Lipidol. 10,
143150 (1999).
Kensler, T. W., Wakabayashi, N. & Biswal, S. Cell
survival responses to environmental stresses via the
Keap1-Nrf2-ARE pathway. Annu. Rev. Pharmacol.
Toxicol. 47, 89116 (2007).
Weidemann, A. & Johnson, R. S. Biology of HIF-1.
Cell Death Differ. 15, 621627 (2008).
Iwakoshi, N. N., Lee, A. H. & Glimcher, L. H. The X-box
binding protein-1 transcription factor is required for
plasma cell differentiation and the unfolded protein
response. Immunol. Rev. 194, 2938 (2003).
Gu, Y. Z., Hogenesch, J. B. & Bradfield, C. A. The PAS
superfamily: sensors of environmental and
developmental signals. Annu. Rev. Pharmacol. Toxicol.
40, 519561 (2000).
Hayden, M. S. & Ghosh, S. Shared principles in
NF-B signaling. Cell 132, 344362 (2008).
Saitoh, T. et al. Negative regulation of interferonregulatory factor 3-dependent innate antiviral
response by the prolyl isomerase Pin1. Nature
Immunol. 7, 598605 (2006).
Covert, M. W., Leung, T. H., Gaston, J. E. & Baltimore, D.
Achieving stability of lipopolysaccharide-induced
NF-B activation. Science 309, 18541857 (2005).
Werner, S. L., Barken, D. & Hoffmann, A. Stimulus
specificity of gene expression programs determined
by temporal control of IKK activity. Science 309,
18571861 (2005).
not discussed here, although some of them (for example,

IFN in host defence and other cellular stressors) must
control inflammation in a module-specific manner,
through transcriptional mechanisms that would be of
great interest to understand.
In addition, we have discussed how transcriptional
modules encode functional programmes of the inflammatory response, and it will be important to further
define these modules and the mechanisms that enable
their autonomous regulation. The identification of
module-specific transcriptional regulators and chromatin modifications is important not only for understanding the organization of this transcriptional programme,
but would also enable the specific manipulation of
various components of the inflammatory response.
Finally, there is a growing awareness that many of the
most prevalent human diseases are associated with pathophysiological chronic inflammation. This type of inflammation is persistent and long-lasting, and is associated
with self-amplifying loops that maintain its expression.
Given the role of chromatin in regulating both dynamic
and stable patterns of gene expression, chronic inflammation is probably associated with a reprogramming
of inflammatory gene expression that is mediated by
alterations to chromatin. Therefore, it will be important
to determine whether chromatin dysregulation underlies
chronic inflammation in many disease settings.
16. Litvak, V. et al. Function of C/EBP in a regulatory

circuit that discriminates between transient and
persistent TLR4-induced signals. Nature Immunol.
10, 437443 (2009).
This paper delineates a transcriptional circuitry
in the LPS-inducible gene expression programme in
macrophages.
17. Friedman, A. D. Transcriptional control of granulocyte
and monocyte development. Oncogene 26,
68166828 (2007).
18. Valledor, A. F., Borras, F. E., Cullell-Young, M. &
Celada, A. Transcription factors that regulate
monocyte/macrophage differentiation. J. Leukoc. Biol.
63, 405417 (1998).
19. Zeng, C. et al. Identification of a nuclear matrix
targeting signal in the leukemia and bone-related
AML/CBF- transcription factors. Proc. Natl Acad. Sci.
USA 94, 67466751 (1997).
20. Gilchrist, M. et al. Systems biology approaches
identify ATF3 as a negative regulator of Toll-like
receptor 4. Nature 441, 173178 (2006).
21. Hoffmann, A., Levchenko, A., Scott, M. L. &
Baltimore, D. The IB-NF-B signaling module:
temporal control and selective gene activation.
Science 298, 12411245 (2002).
22. Basak, S. et al. A fourth IB protein within the NF-B
signaling module. Cell 128, 369381 (2007).
23. Kearns, J. D. & Hoffmann, A. Integrating
computational and biochemical studies to explore
mechanisms in NF-B signaling. J. Biol. Chem. 284,
54395443 (2009).
24. Bernstein, B. E., Meissner, A. & Lander, E. S. The
mammalian epigenome. Cell 128, 669681 (2007).
25. Saccani, S., Pantano, S. & Natoli, G. p38Dependent marking of inflammatory genes for
increased NF-B recruitment. Nature Immunol.
3, 6975 (2002).
One of the first papers to show how a specific
histone modification is coupled to the upregulation
of expression of a subset of LPS-inducible genes.
26. Hazzalin, C. A. & Mahadevan, L. C. Dynamic
acetylation of all lysine 4-methylated histone H3 in the
mouse nucleus: analysis at c-fos and c-jun. PLoS Biol.
3, e393 (2005).
27. Anest, V. et al. A nucleosomal function for IB kinase-
in NF-B-dependent gene expression. Nature 423,
659663 (2003).
28. Yamamoto, Y., Verma, U. N., Prajapati, S., Kwak, Y. T.

& Gaynor, R. B. Histone H3 phosphorylation by IKK-
is critical for cytokine-induced gene expression.
Nature 423, 655659 (2003).
29. Zhou, W. et al. Histone H2A monoubiquitination
represses transcription by inhibiting RNA polymerase
II transcriptional elongation. Mol. Cell 29, 6980
(2008).
30. De Santa, F. et al. The histone H3 lysine-27
demethylase Jmjd3 links inflammation to inhibition
of polycomb-mediated gene silencing. Cell 130,
10831094 (2007).
This paper shows how a histone-modifying
enzyme functions in the regulation of a subset
of LPS-inducible genes.
31. Bernstein, B. E. et al. A bivalent chromatin structure
marks key developmental genes in embryonic stem
cells. Cell 125, 315326 (2006).
32. Hargreaves, D. C., Horng, T. & Medzhitov, R. Control
of inducible gene expression by signal-dependent
transcriptional elongation. Cell 138, 129145 (2009).
33. Becker, P. B. & Horz, W. ATP-dependent nucleosome
remodeling. Annu. Rev. Biochem. 71, 247273
(2002).
34. Lai, D. et al. Induction of TLR4-target genes entails
calcium/calmodulin-dependent regulation of
chromatin remodeling. Proc. Natl Acad. Sci. USA 106,
11691174 (2009).
35. Ramirez-Carrozzi, V. R. et al. Selective and
antagonistic functions of SWI/SNF and Mi-2
nucleosome remodeling complexes during an
inflammatory response. Genes Dev. 20, 282296
(2006).
This paper identifies distinct classes of
LPS-inducible inflammatory genes based on the
requirement for signal-dependent chromatin
remodelling.
36. Kayama, H. et al. Class-specific regulation of proinflammatory genes by MyD88 pathways and IB.
J. Biol. Chem. 283, 1246812477 (2008).
37. Ramirez-Carrozzi, V. R. et al. A unifying model for the
selective regulation of inducible transcription by CpG
islands and nucleosome remodeling. Cell 138,
114128 (2009).
This paper shows that many of the regulatory
properties of rapidly inducible inflammatory genes
are associated with their GC-rich promoters.
REVIEWS
38. Lomvardas, S. & Thanos, D. Modifying gene
expression programs by altering core promoter
chromatin architecture. Cell 110, 261271 (2002).
39. Natoli, G., Saccani, S., Bosisio, D. & Marazzi, I.
Interactions of NF-B with chromatin: the art of being
at the right place at the right time. Nature Immunol.
6, 439445 (2005).
40. Herschman, H. R. Primary response genes induced
by growth factors and tumor promoters. Annu. Rev.
Biochem. 60, 281319 (1991).
41. Huang, Z. Q., Li, J., Sachs, L. M., Cole, P. A. & Wong, J.
A role for cofactorcofactor and cofactorhistone
interactions in targeting p300, SWI/SNF and Mediator
for transcription. EMBO J. 22, 21462155 (2003).
42. Yamamoto, M. et al. Regulation of Toll/IL-1-receptormediated gene expression by the inducible nuclear
protein IB. Nature 430, 218222 (2004).
43. Leung, T. H., Hoffmann, A. & Baltimore, D. One
nucleotide in a B site can determine cofactor
specificity for NF-B dimers. Cell 118, 453464
(2004).
44. Ogawa, S. et al. Molecular determinants of crosstalk
between nuclear receptors and toll-like receptors.
Cell 122, 707721 (2005).
This paper describes signal-specific and
gene-specific inhibition of inflammatory gene
expression by nuclear receptors.
45. Wietek, C., Miggin, S. M., Jefferies, C. A. & ONeill, L. A.
Interferon regulatory factor-3-mediated activation of
the interferon-sensitive response element by Toll-like
receptor (TLR) 4 but not TLR3 requires the p65
subunit of NF-. J. Biol. Chem. 278, 5092350931
(2003).
46. Chen-Park, F. E., Huang, D. B., Noro, B., Thanos, D. &
Ghosh, G. The B DNA sequence from the HIV long
terminal repeat functions as an allosteric regulator of
HIV transcription. J. Biol. Chem. 277, 2470124708
(2002).
47. Ghisletti, S. et al. Cooperative NCoR/SMRT
interactions establish a corepressor-based
strategy for integration of inflammatory and antiinflammatory signaling pathways. Genes Dev. 23,
681693 (2009).
This paper shows repression of partially overlapping
sets of inflammatory genes by two co-repressors.
48. Huang, W., Ghisletti, S., Perissi, V., Rosenfeld, M. G. &
Glass, C. K. Transcriptional integration of TLR2 and
TLR4 signaling at the NCoR derepression checkpoint.
Mol. Cell 35, 4857 (2009).
49. Ogawa, S. et al. A nuclear receptor corepressor
transcriptional checkpoint controlling activator
protein 1-dependent gene networks required for
macrophage activation. Proc. Natl Acad. Sci. USA
101, 1446114466 (2004).
50. Liew, F. Y., Xu, D., Brint, E. K. & ONeill, L. A. Negative
regulation of Toll-like receptor-mediated immune
responses. Nature Rev. Immunol. 5, 446458
(2005).
51. Thanos, D. & Maniatis, T. Identification of the rel
family members required for virus induction of the
human beta interferon gene. Mol. Cell Biol. 15,
152164 (1995).
52. Mostoslavsky, R. et al. Genomic instability and aginglike phenotype in the absence of mammalian SIRT6.
Cell 124, 315329 (2006).
53. Bates, P. W. & Miyamoto, S. Expanded nuclear roles
for IBs. Sci. STKE 2004, pe48 (2004).
54. Kuwata, H. et al. IBNS inhibits induction of a subset
of Toll-like receptor-dependent genes and limits
inflammation. Immunity 24, 4151 (2006).
55. Wessells, J. et al. BCL-3 and NF-B p50 attenuate
lipopolysaccharide-induced inflammatory responses
in macrophages. J. Biol. Chem. 279, 4999550003
(2004).
56. Carmody, R. J., Ruan, Q., Palmer, S., Hilliard, B. &

Chen, Y. H. Negative regulation of Toll-like receptor
signaling by NF-B p50 ubiquitination blockade.
Science 317, 675678 (2007).
57. Hirotani, T. et al. The nuclear IB protein IBNS
selectively inhibits lipopolysaccharide-induced IL-6
production in macrophages of the colonic lamina
propria. J. Immunol. 174, 36503657 (2005).
58. Kuwata, H. et al. IL-10-inducible Bcl-3 negatively
regulates LPS-induced TNF- production in
macrophages. Blood 102, 41234129 (2003).
59. Moore, K. W., de Waal Malefyt, R., Coffman, R. L. &
OGarra, A. Interleukin-10 and the interleukin-10
receptor. Annu. Rev. Immunol. 19, 683765 (2001).
60. Murray, P. J. The primary mechanism of the
IL-10-regulated antiinflammatory response is to
selectively inhibit transcription. Proc. Natl Acad. Sci.
USA 102, 86868691 (2005).
61. Wall, E. A. et al. Suppression of LPS-induced TNF-
production in macrophages by cAMP is mediated by
PKA-AKAP95-p105. Sci. Signal 2, ra28 (2009).
62. Glass, C. K. & Ogawa, S. Combinatorial roles of
nuclear receptors in inflammation and immunity.
Nature Rev. Immunol. 6, 4455 (2006).
63. Giles, K. M. et al. Glucocorticoid augmentation of
macrophage capacity for phagocytosis of apoptotic
cells is associated with reduced p130Cas expression,
loss of paxillin/pyk2 phosphorylation, and high levels
of active Rac. J. Immunol. 167, 976986 (2001).
64. Lee, C. H. et al. Transcriptional repression of
atherogenic inflammation: modulation by PPAR.
Science 302, 453457 (2003).
65. Yeung, F. et al. Modulation of NF-B-dependent
transcription and cell survival by the SIRT1
deacetylase. EMBO J. 23, 23692380 (2004).
66. Kawahara, T. L. et al. SIRT6 links histone H3 lysine 9
deacetylation to NF-B-dependent gene expression
and organismal life span. Cell 136, 6274 (2009).
67. Hu, X. et al. Integrated regulation of Toll-like receptor
responses by Notch and interferon- pathways.
Immunity 29, 691703 (2008).
68. Kincaid, E. Z. & Ernst, J. D. Mycobacterium
tuberculosis exerts gene-selective inhibition of
transcriptional responses to IFN- without inhibiting
STAT1 function. J. Immunol. 171, 20422049 (2003).
69. Hamon, M. A. & Cossart, P. Histone modifications
and chromatin remodeling during bacterial infections.
Cell Host Microbe 4, 100109 (2008).
70. Leng, J., Butcher, B. A., Egan, C. E., Abdallah, D. S. &
Denkers, E. Y. Toxoplasma gondii prevents chromatin
remodeling initiated by TLR-triggered macrophage
activation. J. Immunol. 182, 489497 (2009).
71. Hamon, M. A. et al. Histone modifications induced by
a family of bacterial toxins. Proc. Natl Acad. Sci. USA
104, 1346713472 (2007).
72. Guttman, M. et al. Chromatin signature reveals over a
thousand highly conserved large non-coding RNAs in
mammals. Nature 458, 223227 (2009).
73. Lefevre, P., Witham, J., Lacroix, C. E., Cockerill, P. N.
& Bonifer, C. The LPS-induced transcriptional
upregulation of the chicken lysozyme locus involves
CTCF eviction and noncoding RNA transcription. Mol.
Cell 32, 129139 (2008).
74. Baltimore, D., Boldin, M. P., OConnell, R. M., Rao, D. S.
& Taganov, K. D. MicroRNAs: new regulators of
immune cell development and function. Nature
Immunol. 9, 839845 (2008).
75. Ponting, C. P., Oliver, P. L. & Reik, W. Evolution and
functions of long noncoding RNAs. Cell 136,
629641 (2009).
76. Phillips, J. E. & Corces, V. G. CTCF: master weaver of
the genome. Cell 137, 11941211 (2009).
77. Anderson, P. Post-transcriptional control of cytokine
production. Nature Immunol. 9, 353359 (2008).
78. Hao, S. & Baltimore, D. The stability of mRNA

influences the temporal order of the induction of
genes encoding inflammatory molecules. Nature
Immunol. 10, 281288 (2009).
79. Matsushita, K. et al. Zc3h12a is an RNase essential
for controlling immune responses by regulating
mRNA decay. Nature 458, 11851190 (2009).
80. Foster, S. L. & Medzhitov, R. Gene-specific control of
the TLR-induced inflammatory response. Clin.
Immunol. 130, 715 (2009).
81. El Gazzar, M., Yoza, B. K., Hu, J. Y., Cousart, S. L. &
McCall, C. E. Epigenetic silencing of tumor necrosis
factor during endotoxin tolerance. J. Biol. Chem.
282, 2685726864 (2007).
82. Foster, S. L., Hargreaves, D. C. & Medzhitov, R.
Gene-specific control of inflammation by TLR-induced
chromatin modifications. Nature 447, 972978
(2007).
83. Chan, C., Li, L., McCall, C. E. & Yoza, B. K. Endotoxin
tolerance disrupts chromatin remodeling and NF-B
transactivation at the IL-1 promoter. J. Immunol.
175, 461468 (2005).
84. Odegaard, J. I. et al. Macrophage-specific PPAR
controls alternative activation and improves insulin
resistance. Nature 447, 11161120 (2007).
85. Kouzarides, T. Chromatin modifications and their
function. Cell 128, 693705 (2007).
86. Strahl, B. D. & Allis, C. D. The language of covalent
histone modifications. Nature 403, 4145 (2000).
87. Vermeulen, M. et al. Selective anchoring of TFIID to
nucleosomes by trimethylation of histone H3 lysine 4.
Cell 131, 5869 (2007).
88. Lis, J. T. Imaging Drosophila gene activation and
polymerase pausing in vivo. Nature 450, 198202
(2007).
89. Guenther, M. G., Levine, S. S., Boyer, L. A.,
Jaenisch, R. & Young, R. A. A chromatin landmark
and transcription initiation at most promoters in
human cells. Cell 130, 7788 (2007).
This study shows that RNA polymerase II is paused
at the promoters of many mammalian genes across
the genome.
90. Muse, G. W. et al. RNA polymerase is poised for
activation across the genome. Nature Genet. 39,
15071511 (2007).
91. Zeitlinger, J. et al. RNA polymerase stalling at
developmental control genes in the Drosophila
melanogaster embryo. Nature Genet. 39,
15121516 (2007).
Acknowledgements
We would like to thank D. Hargreaves, S. Foster and S. Smale

for discussions. R.M. is an Investigator at the Howard Hughes
Medical Institute.
DATABASES
UniProtKB: http://www.uniprot.org
2A-HUB | A20 | ATF3 | BCL-3 | Bmp2 | CBP | CCL2 | CCL3 |
CCL5 | C/EBP | C/EBP | CREB1 | CXCL2 | CXCL10 | GCN5 |
HES | HEY | IB | IB | IBNS | IKK | IL-6 | IL-10 | IL-12p40 |
IRAKM | IRF3 | IRF8 | JUN | KDM6B | MSK1 | MSK2 | NCOR |
p50 | p65 | p300 | PCAF | PPAR | PPAR | PU.1 | RBP-J | RCOR |
RUNX1 | SIRT1 | SIRT6 | SMRT | ST2 | TEL | TGF | TNF |
ZC3H12A
FURTHER INFORMATION
Ruslan Medzhitovs homepage:
http://www.med.yale.edu/immuno/fac_medzhitov.html
Tiffany Horngs homepage:
http://www.hsph.harvard.edu/faculty/tiffany-horng
All lInkS ArE ACTIvE In ThE onlInE PdF


Transcriptional Control of The Inflammatory Response PDF

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Transcriptional Control of The Inflammatory Response PDF

Uploaded by

Copyright:

Available Formats

REVIEWS

Transcriptional control of the

Abstract | Inflammation is a multicomponent response to tissue stress, injury and infection,

*Howard Hughes Medical

Inflammation is a fundamental adaptation to the loss

692 | o CToBER 2009 | VoLuME 9

regulators (such as N-ethylmaleimide-sensitive factor 2

Nature Reviews | Immunology

NATuRE REVIEwS | Immunology

VoLuME 9 | o CToBER 2009 | 693

Class III transcription

and/or facilitates its removal from the promoters of target

include Pu.1 (also known as SPI1) and C/EBP, as well

694 | o CToBER 2009 | VoLuME 9

Intracellular localization Function of transcription factors

Responsible for the primary phase of

Integrate signals from

Most are constitutively

Regulate subsequent waves of

Some might specify

Regulate constitutive, as well as

can be divided into a limited number of distinct patterns

Dynamic chromatin remodelling

interplay between these processes in the control of

NATuRE REVIEwS | Immunology

VoLuME 9 | o CToBER 2009 | 695

Small interfering RNA

Another subset of LPS-inducible genes undergoes

696 | o CToBER 2009 | VoLuME 9

b Secondary response gene

Chromatin architecture. Chromatin remodelling 32 can

NATuRE REVIEwS | Immunology

VoLuME 9 | o CToBER 2009 | 697

polymerase II (Pol II) that is phosphorylated on

Co-regulators of the inflammatory response

co-activators have histone-modifying activities and

Box 3 | Transcription initiation and elongation

698 | o CToBER 2009 | VoLuME 9

combined transactivation potential of the two factors

TLR ligands or other

Figure 3 | Control of inflammatory gene expression by co-activators and

indicating that this group of genes can be regulated

Negative regulation of inflammatory genes

NATuRE REVIEwS | Immunology

VoLuME 9 | o CToBER 2009 | 699

LPS-inducible negative feedback loops. Members of the

Negative regulation by anti-inflammatory pathways.

700 | o CToBER 2009 | VoLuME 9

Pathogen-mediated chromatin remodelling. Pathogens

of pathogen virulence factors, so it is possible that the

Additional control mechanisms

NATuRE REVIEwS | Immunology

VoLuME 9 | o CToBER 2009 | 701

Conclusions and future perspectives

Hotamisligil, G. S. Inflammation and metabolic

not discussed here, although some of them (for example,

16. Litvak, V. et al. Function of C/EBP in a regulatory

702 | o CToBER 2009 | VoLuME 9

28. Yamamoto, Y., Verma, U. N., Prajapati, S., Kwak, Y. T.

56. Carmody, R. J., Ruan, Q., Palmer, S., Hilliard, B. &

NATuRE REVIEwS | Immunology

78. Hao, S. & Baltimore, D. The stability of mRNA

We would like to thank D. Hargreaves, S. Foster and S. Smale