REVIEWS

MAPK phosphatases — regulating

the immune response
Yusen Liu, Edward G. Shepherd and Leif D. Nelin
Abstract | Mitogen-activated protein kinase (MAPK) phosphatases (MKPs) are protein
phosphatases that dephosphorylate both the phosphothreonine and phosphotyrosine
residues on activated MAPKs. Removal of the phosphates renders MAPKs inactive, effectively
halting their cellular function. In recent years, evidence has emerged that, similar to MAPKs,
MKPs are pivotal in the regulation of immune responses. By deactivating MAPKs, MKPs can
modulate both innate and adaptive immunity. A number of immunomodulatory agents have
been found to influence the expression of MKP1 in particular, highlighting the central role of
this phosphatase in immune regulation. This Review discusses the properties, function and
regulation of MKPs during immune responses.

Center for Perinatal Research,
Columbus Children’s Research
Institute, Columbus Children’s
Hospital, Department of
Pediatrics, The Ohio State
University College of
Medicine, Columbus,
Ohio 43205, USA.
Correspondence to Y.L.
e-mail: liuy@pediatrics.
ohio-state.edu
doi:10.1038/nri2035
Mitogen-activated protein kinases (MAPKs) are a group
of serine/threonine protein kinases that are highly
conserved across eukaryotic species. MAPKs have an
important role in cellular processes, such as prolifera-
tion, stress responses, apoptosis and immune defence.
In multicellular organisms, MAPKs are necessary for
cellular differentiation, development, learning, memory
and secretion of paracrine and autocrine factors1,2. In
mammalian cells, there are three well-defined MAPK
pathways: the extracellular-signal-regulated kinase
(ERK) pathway, the JUN N-terminal kinase (JNK; also
known as MAPK8) pathway and the p38 (also known as
MAPK14) pathway (reviewed in REF. 1).
The signals that lead to MAPK activation are usu-
ally initiated on the cell surface, primarily by various
membrane-bound receptors2,3. MAPK pathways are
activated through a cascade of sequential phosphory-
lation events, beginning with the phosphorylation
of MAPK kinases (MAPKKs) at two serine residues
by MAPK kinase kinases (MAPKKKs)1 (FIG. 1). Activated
MAPKKs then phosphorylate MAPKs at the adjacent
threonine and tyrosine residues in the conserved Thr-X-
Tyr motif (where the amino acid denoted X corresponds
to glutamic acid in ERK, proline in JNK or glycine in
p38), which is located in a regulatory loop between
the kinase subdomains VII and VIII (REF. 4). The phos-
phorylation of the threonine and tyrosine residues on
MAPKs results in a substantial conformational change
of the protein that increases substrate accessibility and
enhances catalysis5. Activated MAPKs can phosphory-
late a wide array of downstream targets, including pro-
tein kinases and transcription factors, that facilitate the
transcription of MAPK-regulated genes6,7. In addition
to transcriptional regulation, MAPKs can also regulate
gene expression of its targets by altering mRNA stability,
transport and translation2. These signalling cascades are
not only involved in normal cellular processes, but have
also been implicated in the pathology of many diseases,
including cancer1, atherosclerosis8, diabetes9, arthritis10
and septic shock11,12.
Various extracellular signals induce the MAPK
pathways to elicit distinct cellular responses. It has
been shown that MAPK pathways can cooperate with
other ligand-induced signalling pathways to orches-
trate a complex set of cellular events that ultimately
determine the cellular response13. In addition to their
cooperation with other signalling pathways, the MAPK
pathways themselves are subjected to distinct spatio-
temporal regulation by complex feedback and crosstalk
mechanisms 13. Such mechanisms integrate signals
from other pathways to modulate MAPK pathway sig-
nals. Presumably, such variation in the spatiotemporal
properties of the MAPK pathways offers flexibility and
diversity to these pathways14 and, therefore, allows their
participation in determining cellular responses to a host
of environmental cues.
At the molecular level, the MAPK pathways can be
modulated by various mechanisms at almost every step
of the pathway. These mechanisms include receptor
desensitization, dissociation of signalling complexes
from receptors and deactivation of pathway media-
tors. As MAPK pathways are activated through phos-
phorylation, dephosphorylation of kinases, which is
mediated by phosphatases, is likely to be one of the

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Extracellular stimuli the literature published so far, we will use this nomen-
clature in this article to avoid further confusion. This
Cell-surface receptor Review focuses on our most recent understanding of
the function and regulation of MKPs, particularly in the
Plasma membrane
context of immune regulation.

Overview of MKPs
Cytoplasm
Using computational and experimental approaches,
Bhalla et al. have shown that MKPs are pivotal factors in
Membrane- determining the dynamic properties of the MAPK path-
RAS RAC CDC42 RHO associated ways. Their studies indicate that at low concentrations
events
of MKP, MAPKs have a switch-like behaviour (referred
Proliferation Stress Stress to as a bistable state), such that a brief stimulus results
and/or responses responses in sustained MAPK activation. At high concentrations
differentiation
of MKP, MAPKs behave as a proportional response
ERK pathway JNK pathway p38 pathway system over a range of stimulus strengths (referred to
as a monostable state)14. At least ten MKPs have been
RAF MEKK TAK MAPKKKs
identified in mammalian cells so far, with MKP1 being
the archetype of the MKP family. Structurally, all MKPs
P P P have a highly conserved C-terminal catalytic domain
MEK1, MKK4, MKK3, MAPKKs and a less conserved N-terminal region that engages the
MEK2 MKK7 MKK6
P P P cognate MAPKs (FIG. 2).
MKPs can be broadly divided into two distinct
groups on the basis of their subcellular localization and
P P P
ERK JNK P p38 MAPKs patterns of transcriptional regulation. The first group
P P is primarily localized in the nuclear compartment, is
encoded by immediate-early genes, and includes MKP1,
MKP2, DUSP2 (also known as PAC1) and human VH1-
Nucleus
like PTPase-3 (HVH3; also known as DUSP5 or B23).
P P P P Because this group of MKPs is rapidly induced by many
SRF TCF AP1 AP1 ATF2 Transcription of the same stimuli that activate MAPKs, for example
factors
growth factors and stress, it has been proposed that
these MKPs function as a feedback control mechanism
Figure 1 | Schematic diagram of the three mammalian mitogen-activated
protein kinase (MAPK) signalling pathways. Extracellular stimuli activate the for MAPK signalling15,16. By deactivating MAPKs, these
MAPK pathways through mechanisms mediated by GTPases, including RAS, MKPs attenuate the activation of the transcription fac-
RAC, CDC42 (cell-division cycle 42) and RHO (RAS homologue). Once MAPKKKs tors that are the main targets of MAPKs16,17. The second
(MAPK kinase kinases), such as RAF, MEKK (MAPK/ERK kinase kinase) and TAK group of MKPs is not encoded by immediate-early
(TGFβ-activated kinase), are activated, they phosphorylate MAPKKs (MAPK genes, and is either primarily localized in the cytoplasm
kinases) on two serine residues. MAPKKs in turn phosphorylate the MAPKs ERK or localized in both the cytosolic and nuclear compart-
(extracellular-signal-regulated kinase), JNK (JUN N-terminal kinase) and p38 on ments (TABLE 1). Although the expression of some of these
both threonine and tyrosine residues, which results in the catalytic activation of genes can be enhanced, their induction generally takes
these MAPKs. Activated MAPKs can translocate to the nucleus to phosphorylate place at a much slower rate compared with the genes that
a number of transcription factors, such as ternary complex factor (TCF) family
encode the first group of MKPs16,18.
members and components in the activator protein 1 (AP1) complexes, including JUN
and activating transcription factor 2 (ATF2), thereby altering gene transcription. Recent studies have shown that in addition to
TCF forms a complex with serum response factor (SRF) to regulate Fos induction. dephosphorylating MAPKs in specific cellular compart-
AP1 is involved in the transcription of a wide variety of genes. Growth factors ments, MKPs, such as MKP1, MKP3 and HVH3, might
preferentially activate the ERK pathway, whereas stress and inflammatory also serve as anchors for MAPKs and, consequently,
cytokines preferentially activate the JNK and p38 pathways. control the subcellular localization of these crucial
regulators19–21. As the appropriate subcellular localiza-
tion of MAPKs is not only crucial for their activation by
most energy-efficient modes of deactivation. Indeed, upstream kinases but is also pivotal for MAPK engage-
a number of protein phosphatases have been shown ment with downstream targets, the regulation of the
to negatively regulate MAPK pathways, including subcellular localization of MAPKs by MKPs probably
tyrosine, serine/threonine and dual-specificity MAPK affects the function of MAPK pathways. Illustrating the
phosphatases (MKPs). Because MKPs dephosphorylate importance of the localized inactivation of MAPKs by
both phosphothreonine and phosphotyrosine residues MKPs, a recent study showed that Mkp1–/– mice had
on activated MAPKs, they are also known as dual- increased JNK activity in their cell nucleus but not in
specificity protein phosphatases (DUSPs). In fact, DUSP their cell cytosol22. Consequently, these mice are resist-
is the Human Genome Organisation-approved unified ant to diet-induced obesity owing to enhanced energy
nomenclature for this family of phosphatases. However, expenditure, but succumb to glucose intolerance on a
because the nomenclature MKP has been used in most of high-fat diet22.

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DX26(V/L)X(V/I)HCXAG(I/V)SRSXT(I/V)XXAY(L/I)M are stabilized or destabilized after phosphorylation, and

ψψ XRR ψ XXG
NH2 COOH
CDC25- MAPK- Phosphatase catalytic site
homology interacting
2 domain domain
Figure 2 | Structural features of the MKP family. The N-terminal region of all mitogen-
activated protein kinase (MAPK) phosphatases (MKPs) contains a MAPK-interacting
domain with a consensus motif ψψXRRψXXG (where ψ represents a hydrophobic
residue and X is any amino acid), which is flanked by two CDC25-homology 2 domains.
The two arginine residues (R; highlighted in blue) are crucial in the interaction with
MAPKs. Although the exact function of the CDC25-homology 2 domains is unclear, it
has been speculated that these domains might also participate in the interaction
between MKPs and their cognate MAPKs, thereby further refining substrate
specificity95. The three residues highlighted in the phosphatase catalytic site at the
C-terminal region are essential for enzymatic catalysis. The cysteine residue (C) is
required for the nucleophilic attack of the phosphorus on the active MAPK and it forms
a thiol-phosphate intermediate during catalysis. The conserved R residue interacts with
the phosphate group of the MAPK phosphothreonine or phosphotyrosine, which
facilitates transition-state stabilization. The aspartic acid residue (D) enhances catalysis
by functioning as a general acid that protonates the leaving oxygen group.
Compared with other protein phosphatases, all MKPs
have a remarkable specificity for the members of the
MAPK subfamily. However, among these distinct mem-
bers, there are significant differences in their substrate
preferences (TABLE 1). It should be noted that most of the
data on substrate preferences were obtained from tran-
sient transfection assays. Because these experiments rely
on the overexpression of MKPs in immortalized cells,
MKP substrate preferences in these experiments might
be different from those in physiological settings23.
Regulation of MKPs. Although MKPs are active once
they are expressed, their activity can be regulated by at
least three basic mechanisms: transcriptional induction,
phosphorylation-mediated changes in protein stability
and catalytic activation16. Not all MKPs are regulated by
all three mechanisms; some MKPs are inducible, some
some show catalytic activation. The transcription of
many MKPs can be induced (albeit to varying degrees)
in response to extracellular stimuli. In general, the
expression of the nuclear MKPs (MKP1, MKP2, DUSP2
and HVH3) is induced in a robust manner shortly after
extracellular stimuli, such as various growth factors and
cellular stress16. By contrast, induction of the cytosolic
MKPs is generally less robust, and occurs with slower
kinetics16. Although it has been speculated that MAPKs
might have a direct role in the induction of the highly
inducible nuclear MKPs15, this link is still not well
defined.
At least several MKP proteins, including MKP1,
MKP2, MKP3 and MKP7, are post-translationally regu-
lated through phosphorylation. Although phosphory-
lation is not needed for activation of the MKPs, it does
alter their stability24. For example, it has been shown
that when MKP1 is phosphorylated by ERK the half-
life of MKP1 is increased by twofold to threefold24,25.
This increase in half-life would lead to a greater intra-
cellular accumulation of MKP1 and thereby greater
MKP1 activity. A similar finding has recently been
reported for MKP7 (REF. 26). On the other hand, when
ERK phosphorylates MKP3 (an ERK-specific MKP) the
degradation of MKP3 is accelerated27. This would lead
to less MKP3 accumulation in the cell, thereby decreas-
ing its effect. Therefore, it seems that MAPKs can either
stabilize or destabilize MKPs through phosphorylation.
Such phosphorylation-mediated alterations in MKP sta-
bility might represent an important crosstalk mechanism
between distinct MAPK subfamilies.
Finally, the catalytic activities of several, but not all,
MKPs can be substantially enhanced through the inter-
action with their substrate MAPKs. For example, the
interaction of MKP3 with its specific substrate ERK2
enhances the phosphatase activity of MKP3 by almost
30-fold28. Stewart et al. have shown that the crucial
aspartic acid residue in the MKP3 catalytic domain is
nearly 10 Å away from the nucleophilic cysteine and
arginine residues at the catalytic site29, which indicates

Table 1 | Classification of MAPK phosphatases

MKP Species orthologues Substrate specificity Subcellular localization Immediate-early gene References
MKP1 DUSP1, CL100, HVH1, 3CH134, ERP p38 ~ JNK >> ERK Nuclear Yes 15,93–97
MKP2 DUSP4, HVH2, TYP1 ERK ~ JNK >> p38 Nuclear Yes 53,98,99
MKP3 DUSP6, PYST1, RVH6 ERK >> JNK ~ p38 Cytosolic No 100–102
MKP4 DUSP9, PYST3 ERK > p38 > JNK Nuclear and cytosolic No 103,104
MKP5 DUSP10 p38 ~ JNK >> ERK Nuclear and cytosolic No 50,51
MKP7 MKPM, DUSP16 JNK ~ p38 >> ERK Cytosolic No 18,55
MKPX DUSP7, B59, PYST2 ERK >> JNK ~ p38 Cytosolic No 100,105,106
DUSP2 PAC1 ERK ~ p38 >> JNK* Nuclear Yes 53
HVH3 DUSP5, B23 ERK Nuclear Yes 95,107
HVH5 DUSP8, M3/M6 JNK ~ p38 >> ERK Nuclear and cytosolic No 108–110
*Although DUSP2 shows substrate preference for p38 and ERK in transient transfection assays, it prefers JNK as a substrate in vivo23. CL100, human homologue of
MKP1; DUSP, dual-specificity protein phosphatase; ERK, extracellular-signal-regulated kinase; ERP, externally regulated phosphatase; HVH, human VH1-like
PTPase; JNK, JUN N-terminal kinase; MAPK, mitogen-activated protein kinase; MKP, MAPK phosphatase; PAC1, phosphatase of activated cells 1; RVH, rat VH1-like
PTPase; TYP, threonine/tyrosine phosphatase.

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that substrate-binding-induced catalytic activation of
MKP3 might be due to the movement of the aspartic
acid residue closer to the catalytic site (FIG. 2). Movement
of the aspartic acid residue towards the active site ena-
bles the aspartic acid to serve as a general acid, thereby
facilitating dephosphorylation29. The complex regulation
of these phosphatases, together with their distinctive
subcellular localization and substrate preferences, offers
an accurate and flexible mechanism to counterbalance
the actions of the very diverse and multifunctional
MAPK family.
Modulation of innate immune responses by MKPs
One of the most important functions of the innate
immune system is the production of various cytokines,
chemokines and other inflammatory mediators in
response to microbial infection. The production of
many inflammatory mediators, such as tumour-necrosis
factor (TNF), interleukin-1β (IL-1β) and IL-6, as well
as prostaglandin and nitric oxide (synthesized by cyclo-
oxygenase-2 (COX2) and inducible nitric-oxide synthase
(iNOS), respectively), are positively regulated by MAPKs.
In principle, all aspects of the immune response that are
regulated by MAPKs are potentially affected by MKP
proteins. However, until very recently, only a few studies
had been carried out to investigate the function of MKPs
in the immune response. The slow progress in this area
was, at least in part, due to the presumption that many of
the MKPs are functionally redundant and, therefore, that
a deficiency in any single MKP gene would be unlikely
to result in a significant phenotype. However, the genera-
tion of mice that lack Mkp1, Mkp5 or Dusp2 has provided
unequivocal evidence that there are clear non-redundant
functional differences among the distinct MKPs, and that
defects in any of these phosphatases can have signifi-
cant effects on the immune response23,30–34. Moreover,
whereas results from in vivo studies on Mkp1–/– and
Mkp5–/– mice are largely consistent with predictions
drawn from earlier biochemical studies, studies on
Dusp2–/– mice revealed some unexpected results, fur-
ther highlighting the complex functionality of MKPs in
the immune response (TABLE 2). Therefore, this Review
focuses on the functions of these three MKPs in innate
immune regulation.
MKP1. Given the crucial role of p38 and JNK in the
regulation of cytokine biosynthesis and the substrate
preference of MKP1 for these two MAPKs, it was long
suspected that MKP1 might have an important role in
the control of cytokine biosynthesis35. This notion was
strongly supported by several studies using immortal-
ized macrophages, which following lipopolysaccharide
(LPS) stimulation were associated with the induction of
MKP1 expression35. Moderate increases in the amount
of MKP1 accelerated JNK and p38 inactivation and
markedly attenuated the biosynthesis of both TNF and
IL-6. These results provided the first strong evidence
that MKP1 is pivotal for the attenuation of p38 and
JNK signalling during innate immune responses to
LPS, and restrains the production of inflammatory
cytokines35 (FIG. 3).
Mkp1–/– mice are viable and fertile with no detect-
able phenotype36, and studies carried out on both pri-
mary peritoneal and alveolar macrophages from these

Table 2 | Alterations in immunological function caused by the knockout of MKP genes

Knockout Change in Phenotypic changes Refs
mouse MAPK signalling
Innate immunity Adaptive immunity
Mkp1–/– • ↑ p38 and JNK • ↑ TNF, IL-1β, IL-6, CCL2, CCL3, • ↑ Incidence and severity of type II 31–34,
activities CCL4, CXCL2, CXCL10 collagen-induced arthritis 37
• ↑ IL-10 • ↑ Type II collagen antibody
• Hypersensitivity to LPS, ↑ iNOS
expression and NO production,
massive neutrophil infiltration to
lung and liver, severe hypotension
• ↑ Multi-organ failure, ↑ mortality
Mkp5–/– • ↑ JNK activity • ↑ TNF, IL-6, IFNβ, IFNγ • ↓ CD4+ T-cell proliferation 30
• ↑ TGFβ • ↓ TH1 and TH2 cytokine production
• ↓ Incidence and severity of EAE
• ↑ Response to viral infection,
↑ virus-specific CD4+ and CD8+
T-cell numbers
• ↑ IL-2, IL-4, TNF, IFNγ
• ↑ Mortality after secondary viral
challenge
Dusp2–/– • ↑ JNK activity • ↓ Severity of inflammatory arthritis • Not defined 23
• ↓ ERK and p38 in the K/BxN model
activities • ↓ TNF, IL-6, NO, PGE2
• ↓ Survival of bone-marrow-derived
mast cells
↑, increased; ↓, decreased; CCL, CC-chemokine ligand; CXCL, CXC-chemokine ligand; DUSP, dual-specificity protein
phosphatase; EAE, experimental autoimmune encephalomyelitis; ERK, extracellular-signal-regulated kinase; IL, interleukin;
IFN, interferon; iNOS, inducible nitric-oxide synthase; JNK, JUN N-terminal kinase; LPS, lipopolysaccharide; MAPK, mitogen-
activated protein kinase; MKP, MAPK phosphatase; NO, nitric oxide; PGE2, prostaglandin E2; TGFβ, transforming growth factor-β;
TH, T helper; TNF, tumour-necrosis factor.

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Ligand
Plasma or TLR3 TLR4 TLR1, TLR2, TLR5, TLR6,
endosomal TLR7, TLR8, TLR9
membrane
TRAM TIRAP
TRIF MyD88
IκB
p50 p65
NF-κB
mRNA
MAPKs MK2
Nucleus
ERK JNK p38
P MKP1
MKP1
mRNA
AP1-binding site NF-κB-binding site
Figure 3 | The function and regulation of MKP1 during the innate immune
response to microbial infection. During microbial infection, microbial
components interact with TLRs (Toll-like receptors) and activate the downstream
signal transduction pathways through four adaptor proteins that share significant
homology at their TIR (Toll/interleukin-1 receptor) domains. These adaptor
proteins are MyD88 (myeloid differentiation primary-response gene 88), TIRAP
(TIR-domain-containing adaptor protein), TRIF (TIR-domain-containing adaptor
protein inducing interferon-β), and TRAM (TRIF-related adaptor molecule).
Whereas TLR3 signals through TRAM and TRIF adaptors, TLR1, TLR2, TLR5, TLR6,
TLR7, TLR8 and TLR9 use TIRAP and MyD88 adaptors. TLR4 uses all four adaptors.
MyD88 activation leads to the activation of NF-κB (nuclear factor-κB) and MAPK
(mitogen-activated protein kinase) pathways. TRIF engagement also leads to the
activation of NF-κB and MAPK pathways. NF-κB translocates to the nucleus and
initiates cytokine gene transcription. ERK (extracellular-signal-regulated kinase),
JNK (JUN N-terminal kinase) and p38 enhance the expression of pro-inflammatory
cytokines, such as TNF (tumour-necrosis factor), through both transcriptional and
post-transcriptional mechanisms. MAPKs can augment TNF gene transcription by
enhancing AP1 (activator protein 1) activity111 (for simplicity, only activation of AP1
by JNK is illustrated in the diagram). MAPKs, particularly p38, also enhance
cytokine production by enhancing both the stability and the translation
of cytokine mRNA (for simplicity, only p38 is illustrated in the diagram). p38 can
activate MK2 (MAPK-activated protein kinase 2), which in turn enhances cytokine
mRNA stability through phosphorylating the tristetraprolin protein (not shown in
the diagram) and stimulates cytokine mRNA translation. Simultaneously, the same
signal transduction pathways triggered by TLRs, including ERK, also induce the
expression of the MAPK phosphatase 1 (MKP1) gene, resulting in the accumulation
of MKP1. ERK can stabilize MKP1 by phosphorylating it, which therefore
accelerates the accumulation of MKP1 in the nucleus. This leads to the
dephosphorylation of JNK and p38, and the termination of the signals driving TNF
production. In this sense, MKP1 serves as a servocontrol mechanism for cytokine
biosynthesis. The brief delay in MKP1 accumulation offers a window for the
production of TNF. IκB, inhibitor of NF-κB.
206 | MARCH 2007 | VOLUME 7
© 2007 Nature Publishing Group
mice have provided definitive evidence that MKP1
primarily regulates p38 and JNK, but has little effect
on the regulation of ERK31,37. Very similar results were
observed independently in three other laboratories
using bone-marrow-derived macrophages32–34. All four
laboratories showed that deletion of Mkp1 leads to a
substantial increase in the production of a number of
pro-inflammatory cytokines following LPS challenge,
as well as increased chemokine production compared
with wild-type mice31–34. Surprisingly, loss of Mkp1 also
resulted in a substantial increase in the production of
the anti-inflammatory cytokine IL-10 (REFS 31,34). To
understand the global role of MKP1 on gene expression
TNF
in response to a pathogenic stimulus, Hammer et al. used
global microarray analysis to compare the gene expression
TNF profiles in spleen cells from wild-type and Mkp1–/– mice
after LPS challenge in vivo32. They found that among
the approximately 14,000 mouse genes analysed, 608
genes were upregulated in response to LPS in spleen
cells from Mkp1–/– mice. However, nearly threefold more
genes were uniquely upregulated in spleen cells from
Mkp1–/– mice compared with cells from wild-type mice,
and these included the genes encoding the cytokines
IL-6 and IL-10 and a number of chemokines. Therefore,
MKP1 has a key role in limiting gene expression after
LPS challenge in vitro.
Consistent with these findings, Mkp1–/– mice, com-
pared with wild-type mice, also produced substantially
greater amounts of TNF, IL-1β, CC-chemokine ligand 2
TNF
mRNA (CCL2; also known as MCP1), granulocye/macrophage
colony-stimulating factor (GM-CSF), IL-6, IL-10 and
IL-12p70 after LPS challenge in vivo31–34. Despite a
more robust and sustained production of IL-10, the
Mkp1–/– mice showed a considerably higher incidence
of multi-organ failure and mortality compared with
wild-type mice31–34. Previously, it was shown that the
administration of IL-10 together with LPS or shortly
after LPS challenge can prevent lethal endotoxic-shock
syndrome38,39. However, the substantial increase in serum
IL-10 levels in Mkp1–/– mice was apparently ineffec-
tive in protecting these mice. It is possible that, in this
model, IL-10 might not be produced early enough, or in
sufficient amounts, to suppress the toxic effects of the
excessive amounts of pro-inflammatory cytokines38,39.
Alternatively, it is also plausible that part of the anti-
inflammatory function of IL-10 involves the function of
MKP1. In fact, Hammer et al. have found that although
IL-10 does not induce MKP1 expression directly, it pro-
longs MKP1 expression in LPS-stimulated macrophages,
leading to accelerated and long-lasting p38 inactiva-
tion40. Therefore, in the absence of a functional Mkp1
gene, IL-10 might not be able to suppress the production
of inflammatory cytokines and prevent the onset of the
cytokine storm responsible for endotoxic shock.
MKP1 not only functions as a crucial negative
regulator of innate immune responses to LPS, but is
also a pivotal regulator of immune responses to other
microbial components. MKP1 has an important role
in the downregulation of signalling by p38 and JNK
during the innate immune response to CpG (a ligand
of Toll-like receptor 9 (TLR9))33, and to peptidoglycan41
www.nature.com/reviews/immunol

Microarray analysis
A technique for measuring
the transcription of genes.
It involves hybridization of
fluorescently labelled cDNA
prepared from a cell or tissue
of interest with glass slides or
other surfaces dotted with
thousands of oligonucleotides
or cDNA, ideally representing
all expressed genes in the
species.
Endotoxic-shock syndrome
A serious systemic disorder
characterized by severely low
blood pressure and low blood
flow that often leads to
multiple organ failure and
death. It is caused by
lipopolysaccharide (also known
as endotoxin) present in the
blood stream owing to
systemic Gram-negative
bacterial infection.
Endotoxin tolerance
Defined as a transient state of
hyporesponsiveness of the
host or of cultured
macrophages and/or
monocytes to
lipopolysaccharide challenge
following a first exposure to
this stimulus.
Activator protein 1 family
(AP1). A group of transcription
factors forming homodimers or
heterodimers through leucine
zipper interfaces. Although the
prototype AP1 is formed by
FOS and JUN, members of the
ATF and JDP transcription
factor families can also form
heterodimers predominantly
with JUN proteins and bind to
AP1 sites in many gene
promoters.
NATURE REVIEWS | IMMUNOLOGY
(its derivatives are ligands of the nucleotide-binding
oligomerization domain (NOD) proteins 42, TLR2
(REFS 43,44) and potentially TLR1 (REF. 45)). Defects in
Mkp1 gene expression lead to an increase in the pro-
duction of TNF and IL-10 by macrophages stimulated
with ligands of TLR2, TLR3, TLR5 and TLR9 (REF. 33).
Using macrophages deficient in either of the TLR
adaptor molecules MyD88 (myeloid differentiation
primary-response gene 88) or TRIF (Toll/IL-1 recep-
tor (TIR) domain-containing adaptor protein inducing
interferon-β), Chi et al. showed that induction of MKP1
in response to distinct TLR ligands is mediated through
both TLR signalling pathways34. Taken together, these
results indicate that MKP1 provides a crucial negative-
feedback control mechanism to attenuate the activity
of p38 and JNK during the innate immune response to
various microbial components. The time required for
the accumulation of sufficient MKP1 protein to inacti-
vate p38 and JNK offers a crucial window for perpetu-
ating the signals necessary for the production of early
cytokines, such as TNF. In this sense, MKP1 functions
as a servocontrol mechanism that regulates TNF pro-
duction to prevent overproduction of this cytokine in
response to host challenge (FIG. 3). Therefore, when the
innate immune response is activated, immune cells rap-
idly produce TNF, which involves MAPK-dependent
signalling. Induction of MKP1 occurs at a slow rate
and, therefore, TNF production continues unchecked
until sufficient MKP1 has accumulated to turn off
MAPK-dependent signalling. When MAPK-dependent
signalling is turned off, TNF mRNA is rapidly degraded
and the production of TNF ceases shortly after31.
The discovery of MKP1 as a crucial negative regula-
tor of the innate immune response places it in the centre
of the complex negative-regulatory mechanism that
dictates endotoxin tolerance. Biochemically, this impor-
tant task could be carried out through two mechanisms.
First, MKP1 negatively regulate immune responses by
directly dephosphorylating p38 and JNK. Second, MKP1
might compete with both the upstream MAPKKs and
the downstream substrates for binding to p38 or JNK.
MAPKKs, MKPs and downstream substrates (for exam-
ple, MAPK-activated protein kinase 2 (MK2) in the p38
pathway) all bind to the same C-terminal domain of
MAPK46 and we have shown that MK2 and MKP1 bind
to the same acidic domain of p38 (REF. 47). Therefore, by
occupying the common binding domains of JNK or p38,
MKP1 stops signal perpetuation by interference with the
interactions between these MAPKs and their upstream
activators or downstream targets. It has recently been
reported that this type of MKP1-dependent inactiva-
tion of p38 is associated with decreased TNF expression
after a second LPS stimulus, thereby dictating endotoxin
tolerance48,49.
MKP5. MKP5 is an MKP that is localized in both the
cytoplasm and the nucleus and has been shown to
dephosphorylate both JNK and p38 in vitro50,51. MKP5 is
induced in response to LPS stimulation, and overexpres-
sion of MKP5 inhibits activator protein 1 (AP1) reporter
activity, indicating that MKP5 modulates gene expression
© 2007 Nature Publishing Group
REVIEWS
in innate immune cells30. Mkp5–/– mice showed no sig-
nificant phenotype and developed normal lymphoid and
myeloid cells, which indicates that MKP5 is not essential
for development30. Interestingly, an increase in JNK, but
not in p38 activity, was observed in MKP5-deficient
macrophages following LPS stimulation26. Therefore,
although MKP5 inactivates both JNK and p38 in vitro,
MKP5 specifically dephosphorylates JNK in vivo. As
a result of the enhanced JNK activity, MKP5-deficient
macrophages and Mkp5–/– mice showed a more robust
inflammatory response (that is, enhanced TNF and IL-6
production) after LPS challenge30. MKP5 regulates not
only the innate immune response to LPS but also the
responses to peptidoglycan and polyinosinic–polycytidylic
acid (polyI:C; a TLR3 ligand)30. In addition to regulat-
ing the production of inflammatory cytokines, MKP5
also has a role in the regulation of antigen presentation.
Activated antigen-presenting cells (APCs) deficient in
MKP5 stimulated naive T cells to produce IL-2 and
undergo proliferation more effectively than did activated
wild-type APCs30. So, by deactivating JNK, MKP5 indi-
rectly attenuates innate immune responses by inhibiting
cytokine production and antigen presentation.
DUSP2. DUSP2 is expressed only in the haematopoietic
lineage and was originally cloned from human T cells
as an immediate-early gene52. In transient transfection
assays, DUSP2 shows a substrate preference for ERK and
p38 (REFS 53,54). Expression of DUSP2 is induced by TLR
ligands and cytokines in macrophages55. Comprehensive
microarray analysis of human leukocytes has identified
DUSP2 as one of the genes most highly induced after
activation of human mast cells23. Other innate immune
cells, such as eosinophils, neutrophils and macrophages,
also showed considerable induction of DUSP2 after
activation23.
Examination of MAPK activation in macrophages
and mast cells from Dusp2–/– mice revealed a surprising
finding23. Instead of the anticipated increase in ERK
and p38 activities, activated cells from Dusp2–/– mice
showed elevated JNK activity and decreased p38 activ-
ity. Whereas deletion of Dusp2 did not significantly
alter the kinetics of ERK activation in activated macro-
phages, the deletion did attenuate ERK activation in
activated bone-marrow-derived mast cells. Despite the
considerable increase in JNK activity, the production
of cytokines, chemokines and several other inflamma-
tory mediators in DUSP2-deficient macrophages was
actually attenuated23. The phenotype of the cells from
Dusp2–/– mice was not due to functional compensa-
tion by other MKPs, as knockout of Dusp2 did not
result in increased mRNA levels of other genes that
encode MKPs. However, the defect in the production
of inflammatory mediators seemed to be directly due
to the inhibition of ERK and p38 that resulted from the
failure to deactivate JNK, as a pharmacological inhibi-
tor of JNK rescued some of the defects caused by the
knockout of Dusp2. Therefore, Jeffrey et al. concluded
that DUSP2 had a positive regulatory effect on immune
responses that was mediated through the crosstalk
between JNK and ERK23.
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REVIEWS
K/BxN transgenic mouse
A mouse strain formed by
crossing non-obese diabetic
(NOD)/Lt mice with KRN T-cell-
receptor-transgenic mice on
the C57BL/6 background.
As the KRN receptor on the
T cells recognizes a peptide
from the autoantigen glucose-
6-phosphate isomerase, these
mice develop an arthritis that
is mediated, and transferable,
by circulating antibody against
glucose-6-phosphate
isomerase.
208 | MARCH 2007 | VOLUME 7
Although the nature of the crosstalk between the vari-
ous MAPK pathways in this context is still unclear, there
are several possibilities that can be speculated. It is possi-
ble that the JNK pathway might phosphorylate upstream
mediators of the other MAPK pathways, thereby inter-
fering with the activation of these pathways. For example,
JNK1 has been shown to phosphorylate insulin receptor
substrate 1 (IRS1), resulting in desensitization to insu-
lin stimulation9. Alternatively, an inhibitory factor(s)
of ERK and p38, such as a phosphatase(s), could be
induced by the JNK pathway56. Although examination
of DUSP2-deficient cells did not identify increased
mRNA expression for any of the known MKPs23, the
exclusion of MKPs from the crosstalk between JNK and
other MAPKs is probably premature, as MKPs can also
be regulated by alterations in stability and/or catalytic
activation. Clearly, future studies will need to address
the mechanisms involved in the crosstalk between the
MAPK pathways. Regardless of how this crosstalk is
achieved, the interaction between these pathways pre-
dicts that deletion of any given MKP may not only affect
the events directly regulated by its cognate MAPK(s)
but might also have a rippling effect on the biological
processes regulated by other MAPK pathways.
Another interesting finding from this study is that
the survival of Dusp2–/– cells was reduced, presumably
owing to decreased ERK activity. Therefore, DUSP2
has profound positive control over two important
immune cell functions: inflammatory mediator syn-
thesis and survival of innate immune cells. Using the
K/BxN transgenic mouse model of inflammatory arthri-
tis, Jeffrey et al. showed that the knockout of Dusp2
protected mice from the development of inflammatory
arthritis23. As pathogenesis in this model is dependent
on both the generation of pro-inflammatory cytokines
and mast-cell infiltration, removal of the positive effect
of DUSP2 on cytokine production and cell survival
explains this protective effect.
In addition to Mkp1, Mkp5 and Dusp2, other
MKP genes are expressed in innate immune cells.
In mouse macrophages, Mkp2 is expressed at high
levels (Y.L., unpublished observations) and Mkp7 is
strongly induced by LPS and lipid A in RAW264.7
macrophages18. Microarray analyses have indicated
that almost all MKP genes are expressed in innate
immune cells, including dendritic cells, macrophages,
mast cells and eosinophils, although their expression
levels are widely varied23. The widespread expression of
MKP genes indicates that many MKPs might cooper-
ate in the dephosphorylation of MAPKs to ensure an
appropriate control of the MAPK signalling pathways
in various subcellular compartments, and to mount a
proper innate immune response.
The role of MKPs in adaptive immunity
MAPKs have been implicated in T-cell development
and function. For example, ERK1 is necessary for T-cell
proliferation and for the polarization of CD4+ T cells57–59.
Activation of ERK is crucial for IL-2 induction in
T cells through the modulation of transcription fac-
tors, such as nuclear factor of activated T cells (NFAT)
© 2007 Nature Publishing Group
and AP1 (REFS 60–62). Furthermore, the activation of
ERK, JNK and p38 is involved in the cytotoxic response by
CD8+ T cells2. p38 activation is necessary for interferon-γ
(IFNγ) production by CD4+ and CD8+ T cells, and JNK
activation is necessary for IL-4 production by T cells63.
Despite the evidence for a role for MAPKs in T-cell devel-
opment and function, the role for MKPs in the adaptive
immune response is still poorly understood. However, a
number of recent studies have provided some evidence to
propose a role for these phosphatases in the regulation of
adaptive immunity.
DUSP2 is induced in mitogen-stimulated T cells52
and, more recently, microarray analysis has revealed that
the DUSP2 gene is robustly induced by the activation of
T-cell receptors (TCRs) that are expressed by T helper 1
(TH1) and TH2 cells23. In addition to T cells, DUSP2 is also
induced in B cells after receptor crosslinking23. The initial
observations that overexpression of DUSP2 inhibited ERK-
dependent gene expression indicates that DUSP2 might
negatively regulate T-cell signalling54. However, given the
surprising finding that DUSP2 specifically targets JNK
and positively regulates immune responses in vivo23, the
proposed model for DUSP2 function in T-cell signalling
needs to be re-examined. Considering the complex effects
of DUSP2 on the MAPK family and the importance of
MAPKs in T-cell development and function, the knockout
of Dusp2 is likely to have a significant effect on T-cell func-
tion. Whether such an anticipated effect can be confirmed
experimentally remains to be seen.
Recently, it has been shown that Mkp1 –/– mice
have a marked increase in the incidence and severity
of autoimmune arthritis33. This enhanced sensitivity
to collagen-induced arthritis was associated with sig-
nificantly greater levels of systemic pro-inflammatory
cytokines, such as TNF and IL-6, and an increase in
collagen-specific antibodies. As the pathogenesis
of collagen-induced arthritis is dependent on the
production of arthritogenic antibodies against type II
collagen (a process involving both T and B cells),
this study indicates that defects in the expression of
MKP1 might augment the adaptive immune response.
However, it remains unclear at present whether the
apparently enhanced adaptive immune response
observed in Mkp1–/– mice is due to an alteration in
innate immune functions and/or to intrinsic changes
in T-cell or B-cell function. MKP1 is expressed in
T cells and its expression is increased in response to
TCR activation23,64. Therefore, as both JNK and p38
are known to mediate T-cell function, and MKP1 has
been shown to regulate these kinases in innate immune
cells, it would not be surprising if T cells deficient for
MKP1 were functionally defective.
MKP5 expression is higher in CD4+ TH2 cells than
in TH1 cells30, correlating with the stronger activity
of JNK and p38 in T H 1 cells 63,65. Perhaps the most
convincing evidence to support an important role for
MKPs in the regulation of adaptive immunity is pro-
vided by a study of Mkp5–/– mice. Zhang et al. found
that MKP5 was constitutively expressed in naive CD4+
T cells; however its expression was down regulated
24 hours after T-cell activation 30. The studies also
www.nature.com/reviews/immunol

Experimental autoimmune
encephalomyelitis
(EAE). An animal model of the
human autoimmune disease
multiple sclerosis. EAE is
induced in experimental
animals by immunization with
myelin or peptides derived
from myelin. The animals
develop a paralytic disease
with inflammation and
demyelination in the brain and
spinal cord.
Glucocorticoids
A group of compounds that
belongs to the corticosteroid
family. These compounds can
either be naturally produced
(hormones) or synthetic. They
affect metabolism and have
anti-inflammatory and
immunosuppressive effects.
Many synthetic glucocorticoids
(for example, dexamethasone)
are used in clinical medicine as
anti-inflammatory drugs.
Endocannabinoids
A group of endogenous
agonists for cannabinoid
receptors that are present in
animals. They are metabolites
of eicosanoid fatty acids.
NATURE REVIEWS | IMMUNOLOGY
showed that knockout of Mkp5 resulted in increased
JNK activity following TCR activation but had no
effect on either p38 or NF-κB (nuclear factor-κB) in
both T H1 and T H2 cells. Interestingly, CD4 + T cells
from Mkp5 –/– mice showed a reduced proliferative
response after TCR activation, although the produc-
tion of both TH1- and TH2-associated cytokines was
enhanced. Similar to MKP5-deficient CD4+ T cells,
MKP5-deficient CD8 + T cells also produced more
IFNγ and TNF in vitro30. Compared with wild-type
mice, Mkp5–/– mice showed enhanced resistance to
experimental autoimmune encephalomyelitis, which cor-
related with decreased CD4+ T-cell infiltration into
the brains of these mice30. When the role of MKP5
was examined in T-cell-mediated immunity to infec-
tion by inoculating Mkp5–/– and wild-type mice with
lymphocytic choriomeningitis virus (LCMV) there
was no significant difference between wild-type and
Mkp5–/– mice in the clearance of LCMV during the
initial infection30. However, in response to secondary
infection, Mkp5–/– mice showed a minor increase in
the number of virus-specific CD4+ and CD8+ T cells
and these T cells produced more effector cytokines,
including TNF, IFNγ, IL-2 and IL-4. In addition, these
mice had increased mortality30. This study shows that
MKP5 is a positive regulator of cell proliferation,
but a negative regulator of cytokine production in
effector T cells. MKP5 restrains the T-cell responses
during viral infection and protects the host from the
detrimental effects of excessive T-cell responses to
pathogens.
MKP1 regulation by immunomodulatory agents
As MKPs are important regulators of immune responses,
agents that modulate their expression could, at least in
theory, have immunomodulatory properties. Perhaps
the best examples of such modulation are shown by the
induction of MKP1 by glucocorticoids. Glucocorticoids
are important anti-inflammatory drugs that are widely
used for the treatment of chronic inflammatory dis-
eases. Glucocorticoids, particularly dexamethasone, can
inhibit the activity of JNK and p38 and block the pro-
duction of inflammatory cytokines by macrophages66–68.
Dexamethasone was shown to induce MKP1 expression
in mast cells, macrophages and HeLa cells35,69,70. We have
shown that the relative anti-inflammatory potencies of a
group of routinely prescribed synthetic glucocorticoids
were tightly correlated with their capacity to induce the
expression of MKP1 (REF. 37). Recently, using macro-
phages isolated from Mkp1–/– mice, Abraham et al.
showed that MKP1 mediates the inhibitory effects of
dexamethasone on p38 and JNK and that it contributes
to the anti-inflammatory effects of glucocorticoids
in vivo71. These studies support the hypothesis that
induction of MKP1 is part of the anti-inflammatory
mechanism of glucocorticoids. Recently, it was shown
that the endocannabinoid anandamide can protect neu-
rons from inflammatory damage by inducing MKP1
expression in microglial cells, further showing the
central role of MKP1 in the restraint and resolution of
inflammation72.
© 2007 Nature Publishing Group
REVIEWS
Cholera toxin B subunit (CTB), the non-toxic pen-
tamer moiety of cholera toxin produced by the Gram-
negative bacterium Vibrio cholerae, also induces MKP1
expression in macrophages35. CTB has been reported to
suppress the onset of T-cell-dependent autoimmune dis-
eases and to potentiate tolerance in the adaptive immune
system73–77. We found that CTB potently induced MKP1
expression and significantly inhibited JNK and p38
activation, leading to substantial attenuation of TNF
and IL-6 production by LPS-stimulated macrophages35.
These findings indicate that induction of MKP1 expres-
sion could be a potential mechanism responsible for the
immunomodulating properties of CTB.
By contrast, some pro-inflammatory cytokines seem
to enhance their inflammatory responses through the
inhibition of MKP1. IFNγ has been shown to boost the
antimicrobial activity of macrophages and to augment
the production of inflammatory cytokines78–81. We found
that induction of MKP1 by LPS was attenuated in peri-
toneal macrophages in the presence of IFNγ (REF. 31).
This inhibition of MKP1 by IFNγ was associated with
a prolonged activation of p38 and JNK31.
Macrophage migration-inhibitory factor (MIF) is
a potent pro-inflammatory cytokine82. MIF has long
been recognized as a physiological counter-regulator
of the immunosuppressive effects of glucocorticoids83.
However, the mechanisms by which MIF exerts its
regulatory effect remain largely unknown. Recently,
Roger et al. found that MIF alleviated the inhibitory
effect of dexamethasone on TNF and CXC-chemokine
ligand 8 (CXCL8; also known as IL-8) production in a
dose-dependent manner84. Furthermore, induction of
MKP1 by dexamethasone in macrophages was inhibited
by recombinant MIF. Suppression of endogenous MIF
expression resulted in greater MKP1 expression and
restored dexamethasone-mediated inhibition of TNF
production84. Similarly, Aeberli et al. found that MIF
dampens glucocorticoid sensitivity in macrophages
through the inhibition of MKP1, thereby enhancing p38
activity85. These studies indicate that MIF functions in
an autocrine fashion to suppress glucocorticoid-induced
MKP1 expression and can override the inhibition of
glucocorticoids on cytokine production.
Taken together, these studies show that modulation
of MKP1 expression could be an important part of the
molecular mechanisms of immunomodulatory agents
(FIG. 4). Expansion of this line of investigation to other
MKPs and immunomodulatory agents could provide
valuable insight into their mode of action. Moreover, such
studies could reveal new targets for the development of
immunomodulatory drugs.
Concluding remarks
Despite the cloning of the first MKP gene more than
20 years ago86, and the appreciation of the biochemical
function of MKPs as MAPK-specific phosphatases more
than a decade ago15, the physiological functions of these
phosphatases have not been understood until recently.
Although knockout studies have confirmed some of the
predictions drawn from biochemical studies, they have
also revealed many surprising contradictions of earlier
VOLUME 7 | MARCH 2007 | 209
REVIEWS

Pro-inflammatory
Extracellular
inflammatory insult
cytokines
IFNγ, MIF – times be difficult to detect. Furthermore, the crosstalk
– MAPKs
MKP1
p38 and JNK
+
Anti-inflammatory
factors +
Glucocorticoids, Pro-inflammatory
IL-10, CTB, cytokines
anandamide
+
Inflammatory
response
Figure 4 | Regulation of MKP1 expression by
immunomodulatory agents. Anti-inflammatory and/or
immunosuppressive agents, such as glucocorticoids, IL-10
(interleukin-10), the endocannabinoid anandamide, and
CTB (cholera toxin B subunit) induce and/or augment
MKP1 (mitogen-activated protein kinase (MAPK)
phosphatase 1) expression, which leads to the inhibition of
the p38 and JNK (JUN N-terminal kinase) pathways and
consequently the attenuation of inflammatory responses.
By contrast, pro-inflammatory cytokines, such as IFNγ
(interferon-γ) and MIF (macrophage migration-inhibitory
factor), inhibit MKP1 expression, which leads to prolonged
p38 and JNK pathway signalling and consequently
enhanced inflammatory responses.
observations. It is almost certain that with the generation
of knockout mice for other MKP genes, novel functions of
these MKPs will be discovered. Although the under-
standing of the functions of MKPs is far from complete,
it has become clear that the phenotypes of various MKP
knockout mice are not the simple ‘inverse’ correlates of
individual MAPK loss-of-function effects. For example,
after TCR activation, CD4+ T cells that are deficient in
JNK had a more robust proliferative response and pro-
duced more TH2 cytokines, including IL-4 (REF. 87). By
contrast, CD4+ T cells that are deficient for MKP5, a JNK
phosphatase, have a reduced proliferation response but
an enhanced production of cytokines, including IL-4
and IFNγ (REF. 30). The apparent discordance between
the phenotypes of MAPK- and MKP-deficient mice is
probably due to the fact that MKPs can simultaneously
dephosphorylate multiple MAPKs, although subtle
effects of a given MKP on a specific MAPK might some-
between the various MAPK pathways also contributes to
the discordance between the phenotypes of these mice.
It is worth noting that, although both MKP5 and DUSP2
regulate JNK, their knockout in mice resulted in almost
completely opposite phenotypes: knockout of Mkp5
enhanced the production of inflammatory cytokines,
whereas knockout of Dusp2 attenuated the synthesis of
inflammatory cytokines23,30. Several factors might con-
tribute to the differences in the phenotypes of various
MKP-deficient mice, including differences in subcellular
localization, expression patterns, substrate preference and
other biochemical properties of these phosphatases. An
important challenge in the field of immunology is to
understand the dynamic interaction between multiple
MKPs in the control of immune defence in relation to
various MAPKs. As dysregulation of the immune system
is involved in a wide variety of human diseases, includ-
ing septic shock, rheumatoid arthritis and Crohn’s
disease, it would be important to investigate whether
any of the inflammatory diseases are associated with
abnormal MKP gene expression either owing to unique
polymorphisms or to mutations.
In addition, MKPs are widely anticipated to participate
in various physiological and pathophysiological processes,
including atherosclerosis, diabetes and cancer. For this
reason, future functional studies on MKPs are likely to
expand to more disease models. This is already evident for
MKP1, as a recent study has shown that MKP1 is essential
for metabolic homeostasis22. Also, Wang et al. have shown
that MKP1-deficient embryonic fibroblasts undergo apop-
tosis more readily than wild-type cells after exposure to
cisplatin88, a chemotherapeutic drug widely used in cancer
treatment. As an increase in MKP1 is frequently observed
in various human cancers89–92, selective inhibition of the
expression or activity of MKP1 might improve the effi-
cacy of cancer chemotherapy. Clearly, further studies of
the role and regulation of MKPs might not only facilitate
our understanding of the complex regulation of MAPKs
in specific biological processes and their involvement in
various human diseases, but also reveal new drug targets
for the treatment of these diseases.

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NATURE REVIEWS | IMMUNOLOGY
Reference 31–34 were the first reports to show
that MKP1 is a crucial negative regulator of p38
and JNK, and has a pivotal role in the regulation
of the inflammatory responses to bacterial
components. These papers also show that Mkp1–/–
mice are profoundly sensitive to endotoxin.
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Acknowledgements
Owing to space limitations, many important studies could not
be included in this Review, and we apologize for any such over-
sight. The work in our laboratory was supported in part by
grants from the US National Institutes of Health. We are grate-
ful to M. Gorospe and K. Liu for editing the original manu-
script. We also want to thank the members of our laboratory
and colleagues in the field for their helpful suggestions.
Competing interests statement
The authors declare no competing financial interests.
DATABASES
The following terms in this article are linked online to:
Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.
fcgi?db=gene
DUSP2 | ERK | JNK | MKP1 | MKP2 | MKP5 | p38
FURTHER INFORMATION
Yusen Liu’s homepage: http://columbuschildrens.com/gd/
applications/controller.cfm?page=3812&pname=bio&rID=95
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