DUSP Meet Immunology: Dual Specificity MAPK in Control of the Inflammatory Response

This information is current as Roland Lang, Michael Hammer and Jörg Mages of September 29, 2021. J Immunol 2006; 177:7497-7504; ; doi: 10.4049/jimmunol.177.11.7497 http://www.jimmunol.org/content/177/11/7497 Downloaded from

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JOURNAL OF IMMUNOLOGY

BRIEF REVIEWS

DUSP Meet Immunology: Dual Specificity MAPK Phosphatases in Control of the Inflammatory Response1 Roland Lang,2 Michael Hammer, and Jo¨rg Mages

The MAPK family members p38, JNK, and ERK are all promoters of e.g., Il6, Tnfa, and many other that are up- activated downstream of innate immunity’s TLR to in- regulated in response to TLR ligation. duce the production of cytokines and inflammatory medi- The three major subfamilies of MAPK that are expressed in ators. However, the relative intensity and duration of the the immune system are p38, ERK, and JNK (1). All three activation of different MAPK appears to determine the MAPK are phosphorylated on the and tyrosine resi- type of immune response. The mammalian genome en- dues of the shared TxY motif within minutes after TLR stimu- 3 codes a large number of dual specificity phosphatases lation of macrophages and dendritic cells (DC) , as shown early Downloaded from (DUSP), many of which act as MAPK phosphatases. In on for the TLR4 ligand LPS (2) and CpG DNA that activates this study, we review the emergence of several DUSP as TLR9 (3, 4). Rapid transduction of the signal from TNFR-as- genes that are differentially expressed and regulated in im- sociated factor 6 to the MAPK is achieved through the sequen- mune cells. Recently, a series of investigations in mice de- tial activation of upstream MAP3K and MAPK (re- ficient in DUSP1, DUSP2, or DUSP10 revealed specific- viewed in Ref. 1). http://www.jimmunol.org/ ity in the regulation of the different MAPK , and Downstream of the MAPK, a large number of substrates that defined essential roles in models of local and systemic in- are serine/threonine-phosphorylated have been defined, includ- ing transcription factors of the ATF/CREB and AP-1 family, flammation. The DUSP family is proposed as a set of mo- kinases such as Mapkapk2/MK2 and RSK, and proteins con- lecular control devices specifying and modulating MAPK trolling mRNA stability and translation. Although there is signaling, which may be targeted to unleash or attenuate some overlap in the target proteins of MAPK, prototypic-spe- innate and adaptive immune effector functions. The cific downstream mediators have also been defined using spe- Journal of Immunology, 2006, 177: 7497–7504. cific pharmacological inhibitors. These studies demonstrated

the importance of MAPK activation in cytokine and chemokine by guest on September 29, 2021 nnate immune cells respond swiftly to the presence of spe- expression in general, and provided many specific exam- cific ligands signaling infectious danger that they recog- ples of genes that are regulated preferentially by one or the other I nize through pattern recognition receptors. Activation of MAPK. For example, IL-10 production was inhibited by the TLR, e.g., by LPS of Gram-negative bacteria, lipopeptides de- Map2k1/MEK1 inhibitor U0126 (5, 6), whereas IL-12 expres- rived from Gram-positive bacteria or immunostimulatory CpG sion was suppressed by inhibition of p38 with SB203580 (5, 7). DNA, induces the expression of cytokines, chemokines, and Furthermore, higher IL-12 production from DC than from other inflammatory mediators within less than 1 h. Two major macrophages after stimulation was inversely correlated with dif- signaling pathways are activated downstream of the TLR-in- ferences in the amount of ERK activation between the cell types duced Myd88-IL-1R-associated -TNFR-associated fac- (8). The concept that the pattern of MAPK activation may de- tor 6 complex, which are essential for such a rapid response, and termine the type of cytokine output was further supported by both involve the activation of latent transcription factors as fol- investigations into the activation of MAPK by different TLR lows: 1) activation of the I␬B kinase complex targets I␬B for ligands inducing reciprocal patterns of secretion of the immu- degradation leading to nuclear translocation of active NF-␬B; nosuppressive cytokine IL-10 and the Th1-driving IL-12 (9, and 2) the MAPK pathway, a cascade of phosphorylation events 10). High levels of IL-10 along with low IL-12 production in that primarily results in the posttranslational activation of tran- response to TLR2 stimulation were shown to correlate with scription factors like CREB and AP-1. Both pathways synergize strong ERK activation, whereas TLR4, TLR5, or TLR9 ligands in inflammatory through coordinate binding of preferentially activated p38 and induced more IL-12 (9, 10). transcription factors to ␬B and AP-1 sites found together in the Through the use of ERK1- and Fos-deficient macrophages, a

Institute of Medical Microbiology, Immunology and Hygiene, Technical University Mu- 2 Address correspondence and reprint requests to Dr. Roland Lang, Institute of Medical Mi- nich, Immunology and Hygiene, Munich, Germany crobiology, Immunology and Hygiene, Technical University Munich, Immunology and Hy- giene, Trogerstrasse 30, Munich 81675, Germany. E-mail address: [email protected] Received for publication July 18, 2006. Accepted for publication August 28, 2006. 3 Abbreviations used in this paper: DC, dendritic cell; MKP, MAPK ; DUSP, The costs of publication of this article were defrayed in part by the payment of page charges. dual specificity phosphatases; MKB, MAPK binding domain; LCMV, lymphocytic cho- This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. riomeningitis virus. Section 1734 solely to indicate this fact. 1 The work performed in the Lang laboratory was supported by the Deutsche Forschungs- gemeinschaft (SFB 576, TP 11 and Grant LA 1262/4-1) and the Bundesministerium fu¨r Bildung und Forschung (NGFN-2 Grant 01GS0402).

Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$02.00 7498 BRIEF REVIEWS: DUSP MEET IMMUNOLOGY pathway could be delineated that controls the ratio of IL-10 vs The biochemistry and structural biology of DUSP proteins IL-12 production with strong ERK activity stabilizing and en- have been recently reviewed (15, 20) and are therefore touched hancing the transcription of Fos that in turn supports IL-10 on in this study only briefly. The presence or absence of MKB, production and inhibits IL-12 (11). Similar conclusions could DUSP, and additional N- or C-terminal domains provides a be made from studies showing Th-2 type adjuvant activity of reasonable basis for grouping DUSP-MKP into four different TLR2 ligands in vivo (12) and IL-10-promoting effects of types (Table I) (15). The subcellular localization and preference ERK-activation by Leishmania phosphoglycans (13). Thus, the for one or the other MAPK as a substrate have also been used to MAPK pathway is used in innate immunity not only to deliver subdivide the DUSP family (14, 20); however, these are not the alarm signals from TLR on fast-track to the nucleus, but always well-defined and may depend on cell-type, activation also it provides a means to translate the nature of the stimulus state, and the presence of interacting proteins. into appropriate responses by balancing the strength of individ- The 3D structure of the catalytic DUSP domain has been ual MAPK signals. The impact of this preferential activation, solved for DUSP6/MKP-3, DUSP2/PAC-1, and DUSP3/ and the notion that in addition to the intensity the kinetics of VHR, revealing that for the atypical DUSP3 it is in a catalyti- MAPK activation will determine the cellular response to stim- cally active conformation (reviewed in Ref. 15). In contrast, in ulation, leads us to the question how MAPK activation is in- the absence of substrate, the catalytic domain of DUSP2 and hibited or terminated. DUSP6 is in a disordered state. As shown for DUSP6, binding to the substrate ERK2 MAPK then strongly increases the cata- Down-regulation of MAPK signaling: dual specificity phosphatases lytic activity (21). The type III MKP DUSP10/MKP-5 con- Downloaded from (DUSP) and other MAPK phosphatases (MKP) tains a unique N-terminal domain of unknown function that is Inactivation of MAPK occurs primarily through dephosphory- suspected to contain regulatory sites (22). In contrast to lation of the TxY motif. Because MAPK have to be phosphor- DUSP6, the catalytic activity of DUSP10 is not increased by ylated on both threonine and tyrosine residues for kinase activ- binding to p38 or JNK (22). The larger type IV MKP DUSP8/ ity, inactivation can be brought about by members of different VH5 and DUSP16/MKP-7 have a C-terminal region with a phosphatase families. MKP include serine-threonine phospha- number of interesting features including proline/glutamine/ http://www.jimmunol.org/ tases (PP2A and PP2C), the tyrosine phosphatases PTPN5, serine/threonine rich, nuclear localization, and leucine-rich nu- PTPN7, and PTPRR (14, 15), and members of the DUSP fam- clear export sequences that play a role in stability of the , ily that is the focus of this study. (A confusing number of syn- interaction with scaffold proteins, and control nuclear-cyto- onyma exists for some of the DUSP genes or proteins. We ad- plasmic shuttling of the protein (23–27). vocate the use of the official gene symbol that is also the abbreviation of the protein. In Table I and on first appearance Patterns of DUSP expression: changes during development, between cell in the text, the most common synonyms are also given.) All types, and in response to external stimuli

DUSP genes encode a catalytic domain harboring a signature In contrast to their substrate MAPK that are expressed ubiqui- by guest on September 29, 2021 HCxxxxxR motif. Of the 30 protein-coding DUSP genes tously, many DUSP genes show regulated expression during de- found in the (16), 11 are bona fide MKP be- velopment, in a cell type-specific manner or in response to cel- cause in addition to the DUSP domain they contain a MAPK lular activation. A good example for the latter is the prototypic binding domain (MKB). The 19 atypical DUSP are much MKP, DUSP1/MKP-1, that was cloned as immediate-early smaller proteins that lack such a MKB, but may still function as gene 3CH134 from serum stimulated human fibroblasts (28, MKP as already demonstrated for DUSP14/MKP6 (17), 29). Similarly regulated by growth factors or in response to cell DUSP3/VHR (18), and DUSP22/VHX (19). Although more stress are DUSP2/PAC1, DUSP4/MKP-2, and DUSP5/VH3. atypical DUSP may turn out to deactivate MAPK, most seem to DUSP9/MKP-4 is highly expressed in the developing liver and have unrelated substrates including RNA in the case of placenta, but at low levels in other organs, illustrating develop- DUSP11/PIR (16). mentally regulated expression (30, 31).

Table I. Classification of DUSP MKP The Journal of Immunology 7499

The availability of microarray technologies was the prerequi- els to date, strong phenotypes were observed that suggest a site for the identification of DUSP as differentially regulated surprising degree of nonredundancy in the function of individ- genes under many different experimental conditions through ual DUSP genes (Table II). large scale gene expression profiling. Individual DUSP were found up-regulated in various cancers, in response to hypoxia, DUSP1/MKP-1: from no phenotype to molecular brake in heat shock, and other perturbations of cells and tissues. Of im- inflammation portance, DUSP have surfaced in several studies investigating The first DUSP MKP was discovered as immediate early gene innate and adaptive immune responses. Kovanen et al. (32, 33) in the fibroblast serum response and initially thought to dephos- analyzed T cell transcriptional responses to cytokine signaling phorylate ERK and only later shown to deactivate MAPK in the through the common ␥-chain and identified DUSP5/VH3 and order p38ϾJNKϾϾERK (41). This initial misconception may DUSP6/MKP-3 as up-regulated by IL-2, IL-7, and IL-15. Tan- also underlie the failure to investigate the effect of DUSP1-de- zola and Kersh (34) performed a real-time PCR profile of ficiency on the different MAPK more closely in the first descrip- DUSP expression during thymic development that showed ex- tion of gene targeted mice. From the apparent health of the pression and regulation of 7 of 10 DUSP genes at various stages mice and the unaltered kinetics of ERK activation, it was con- of T cell development and following stimulation of the TCR cluded that DUSP1 does not have nonredundant functions Ϫ Ϫ complex. In a comprehensive microarray experiment of human (42). Indeed, a recent analysis of MEFs from DUSP1 / mice leukocyte subsets, Jeffrey et al. (35) analyzed the regulation of showed enhanced phosphorylation of p38 and JNK, but not

DUSP genes following activation of B cells, T cells, mast cells, ERK, after osmotic stress and anisomycin, that caused increased Downloaded from eosinophils, macrophages, and DC, and found high levels of cell death (43). induction for the nuclear MKP DUSP1, DUSP2, DUSP4, and DUSP1/MKP-1 is expressed in many hemopoietic and epi- DUSP5 in activated immune cells. Mining of transcriptome thelial cell types, and up-regulated in response to hypoxia (44), datasets from primary mouse macrophages stimulated with LPS heat shock (45), several growth factors, and in various malig- or the RAW 264.7 macrophage cell line after activation with a nancies. In macrophages, the first detection of DUSP1 mRNA set of TLR ligands, our laboratory identified DUSP1, DUSP2, was reported in Listeria-infected cells (46). Celada and col- http://www.jimmunol.org/ and DUSP16 as the most strongly induced MKP; thus, there is leagues (47, 48) then showed that DUSP1 is induced by signal- substantial overlap between these studies in the human and ing through the M-CSF receptor as well as in response to LPS, mouse system (36, 37). Finally, genome-wide analyses of the and additionally demonstrated the involvement of PKC in this host pathogen interaction have revealed induction of several process. TLR stimuli increase DUSP1 expression through DUSP family members in macrophages infected with mycobac- MyD88- or, in the case of poly(I:C), TRIF-dependent signaling teria (38), Gram-negative and -positive bacteria (39), and virus- (49). Whether DUSP1 is a NF-␬B-dependent target of TLR infected HeLa cells (40). signaling has not been addressed. MAPK signaling controls

DUSP1 expression at various levels. In fibroblasts, activation of by guest on September 29, 2021 Defining essential functions for DUSP in immunity: the examples of the JNK pathway, but not of ERK, resulted in increased DUSP1, DUSP10, and DUSP2 DUSP1 mRNA (50). Similarly, inhibition of MEK-1 by During the first decade of research into DUSP-MKP, the bio- PD98059 did not interfere with LPS-induced expression of chemistry of the interaction with MAPK was elucidated for DUSP1 in macrophages (47, 48). However, the role of ERK some members in great detail. Much less is known about the signaling in DUSP1 mRNA expression is not entirely clear, be- physiological roles of the individual DUSP, which is only be- cause the MEK-1 inhibitor U0126 was reported to block LPS- ginning to be revealed through the generation and phenotypic induced increases of DUSP1 at the mRNA and protein level analysis of gene-targeted mice. Given the large number of (51). Although TLR signaling activates the DUSP1 promoter, DUSP-MKP, often coexpressed in one cell type, redundancy mRNA levels may also be controlled by prolonging the very and functional compensation could be expected when just a sin- short half-life of the transcript (36). ERK-dependent signals gle DUSP gene is inactivated. As reviewed in the following sec- also increase the stability of DUSP1 protein through phosphor- tions, for the DUSP-KO mice studied in immunological mod- ylation (52, 53). Consistent with a negative regulatory function

Table II. Immunologically relevant DUSP family members

Phosphatase Inducing Stimuli Cell Types KO Phenotype (Ref.)

DUSP1 (MKP-1) Growth factors, LPS, Macrophages, microglia, Increased production of cytokines, PGN, dexamethasone, mast cells, fibroblasts higher susceptibility to heat shock, hypoxia, endotoxic shock (49, 59–61),

H2O2, endocannabinoids and arthritis induction (61) DUSP2 (PAC-1) Growth factors, heat T and B cells, mast cells, Reduced cytokine production, shock, LPS, phorbol macrophages, protected from inflammatory esters neutrophils arthritis (35) DUSP5 (VH3) IL-2, growth factors, heat T cells, fibroblasts Not reported shock DUSP10 (MKP-5) LPS, peptidoglycan, Macrophages, T cells Increased cytokine production, poly(I:C) decrease in T cell proliferation, protected from EAE, immunopathology in LCMV rechallenge (65) 7500 BRIEF REVIEWS: DUSP MEET IMMUNOLOGY for DUSP1 in macrophage activation, anti-inflammatory glu- DUSP10/MKP-5: acting on innate and adaptive responses cocorticoids increase DUSP1 expression in macrophages, and DUSP10/MKP-5 is the only member of the type III group of mast cells at the mRNA and protein level (36, 54–56). Re- DUSP-MKP, carrying an additional N-terminal domain of cently, we found (36) that the immunosuppressive cytokine poorly characterized function that may control its cytoplasmic IL-10 enhanced and prolonged DUSP1 expression in TLR- or nuclear location (22). JNK and p38 MAPK appear to be the stimulated macrophages, acting in synergy with dexametha- preferred substrates of DUSP10 (22). Although DUSP10 is ex- sone. Finally, the anti-inflammatory effects of the endocan- pressed at much lower levels in immune cells compared with nabinoid anandamide on microglia have recently been many other DUSP, as judged from microarray data, gene tar- correlated to up-regulation of DUSP1 protein levels, sug- geting in mice revealed an interesting phenotype with distinct gesting that signaling through the CB2 receptor is another functions for DUSP10 in innate, and adaptive immunity (Fig. pathway that leads to dampened MAPK activation through 1) (65). DUSP10 is inducible by TLR stimulation in macro- increased DUSP1 levels (57). phages, which showed increased activation in its absence in A negative effect of DUSP1 on macrophage activation was terms of elevated cytokine production in vitro and in vivo, al- suggested by overexpression of DUSP1, which was shown in a though the difference does not seem to be as big as in Ϫ Ϫ ϩ number of studies to inhibit phosphorylation of MAPK and the DUSP1 / mice. In CD4 T cells, DUSP10 is constitutively production of the cytokines TNF-␣ and IL-6 in response to di- expressed but down-regulated 24 h after TCR activation. In the verse TLR stimuli (51, 55, 58). A requirement for DUSP1 as a absence of DUSP10, Th cells activate JNK more strongly early physiological regulator of MAPK activation and cytokine pro- after activation. Although DUSP10-deficient T cells produced Downloaded from duction in macrophages was then demonstrated by a series of strikingly increased amounts of both Th1 and Th2 cytokines, Ϫ Ϫ studies that used DUSP1 / mice generated in the Bravo lab- their Ag-specific proliferation was impaired, consistent with an Ϫ Ϫ oratory (49, 59, 60), or an independently created DUSP1 / inhibitory role for JNK on T cell growth observed earlier (66). mouse line (61). Together, these studies show that p38 MAPK Impaired T cell expansion in DUSP10-deficient mice is also the is the primary target of DUSP1 in activated macrophages, fol- likely cause of an amelioration of disease symptoms in the http://www.jimmunol.org/ lowed by JNK with no or very little effect on ERK activation. MOG-induced EAE model, where brain infiltration by Th cells DUSP1-deficient macrophages secrete increased amounts of was abrogated nearly completely. Finally, in viral lymphocytic TNF-␣, IL-6, and IL-10 after stimulation with TLR-ligands. In choriomeningitis virus (LCMV) infection, strongly enhanced ␥ the high-dose LPS shock model in vivo, the absence of DUSP1 production of the T cell-derived cytokines IL-2, IFN- , IL-4, ␣ renders mice highly susceptible to the lethal effects of endo- and TNF- upon secondary infection resulted in the immune- toxin, with a corresponding, substantially elevated production mediated death of DUSP10-deficient mice. Contrary to what of certain cytokines and mediators. Consistent with the lethal might be expected given the reduced proliferation of T cells in Ϫ Ϫ outcome, DUSP1 / mice displayed the hallmarks of septic vitro, the frequency of LCMV-reactive CD8 and CD4 T cells shock, such as depressed circulation, kidney failure, and inflam- was not reduced in the absence of DUSP10. This discrepancy by guest on September 29, 2021 may be explained by the increased APC function of matory infiltrates in the lung and other tissues, much more pro- Ϫ/Ϫ nounced than the surviving wild-type mice (60). Salojin et al. DUSP10 innate immune cells that compensated for T cell (61) further demonstrated in a model of autoimmune disease autonomous growth-inhibitory effects (Fig. 1). that collagen-induced arthritis is markedly more severe in DUSP2/PAC1: from feedback inhibition to driving force of DUSP1-deficient mice, with increased joint swelling and pro- inflammation duction of IL-6 and TNF-␣ . DUSP1 is therefore an essential Cloned in 1993 as an immediate early gene from TCR-acti- endogenous negative regulator of the systemic and local innate vated T cells (67), DUSP2/PAC-1 localizes to the nucleus and inflammatory response, phenotypically similar in effect to the primarily inactivates p38 MAPK and ERK in vitro (68). cytokine IL-10 (62, 63) or the phosphatase SHIP (64). Of note, DUSP2 was found expressed in malignant tissues where high however, not all cytokine and chemokine responses to the chal- levels correlated with poor prognosis (69). It was also described lenge with LPS are dysregulated in the absence of DUSP1, be- as a transcriptional target of p53 that is required for the induc- ␥ cause serum levels of IFN- , IL-12p40, and IP-10 after LPS tion of in a colon cancer cell line (70). In another challenge were comparable or even reduced. Moreover, mi- study, DUSP2 expression was found to be controlled by ERK croarray analysis of spleen RNA revealed at the genome-wide activation (71). In nontransformed cells, the expression of level that DUSP1 controls a subset of LPS-induced genes (59, DUSP2 appears to be restricted predominantly to the hemo- 60). An interesting aspect of these data is the counterintuitive, poietic lineages, where it is highly inducible in macrophages, overwhelming release of IL-10 in the absence of DUSP1, which mast cells, eosinophils, B, and T cells by activation of Ag or Fc might be expected to bring about down-regulation of the in- receptors (35). This distinguishing feature of DUSP2 may al- flammatory reaction but obviously fails to do so. Although el- ready indicate a special function for this phosphatase in im- evated levels of known IL-10 induced genes (37) such as mune cells. Indeed, the recently reported (35) phenotype of the Ϫ Ϫ SOCS3, NFIL3, or Bcl-3 suggest intact IL-10 signaling in DUSP2 / mouse confirmed a significant role in the immune the absence of DUSP1, an essential fraction of IL-10-in- system, although the results contradicted expectations and in- duced macrophage deactivation may therefore depend on troduced new twists into the tale of MAPK regulation by functional DUSP1. The mutual regulation of expression be- DUSP-MKP. Similarly to what was observed in the case of Ϫ Ϫ tween IL-10 and DUSP1 is connected in a module with p38 DUSP1 or DUSP10, the immune system of DUSP2 / mice MAPK (Fig. 1), whose contribution to IL-10 expression was develops normally. Contrasting to the effects of DUSP1 and Ϫ Ϫ also recently substantiated by work from the Ivashkiv and DUSP10 deficiency, DUSP2 / macrophages and mast cells colleagues (6) laboratory. produced fewer inflammatory mediators after stimulation via The Journal of Immunology 7501 Downloaded from http://www.jimmunol.org/ by guest on September 29, 2021

FIGURE 1. Schematic overview: regulation of immune cell activation by DUSP1 (A), DUSP2 (B), and DUSP10 (C). Selectivity for the different MAPK and regulation of transcriptional responses are shown as described in the text. A, DUSP1 expression in macrophages is synergistically induced by TLR and IL-10 or receptor signaling. DUSP1 acts primarily on p38 MAPK, thereby limiting the activity of CREB and AP-1 transcription factors and controlling the expression of a subset of LPS target genes. B, Control of JNK-ERK cross-talk by DUSP2 in mast cells and macrophages. DUSP2 is induced in macrophages by TLR ligands and in mast cells by Fc␧RI ligation. DUSP2 protein associates MAPKs and blocks JNK-mediated inhibition of ERK activation. In effect, DUSP2 increases expression of inflammatory genes in both cell types. C, Impact of DUSP10 on innate and adaptive immune cells. In macrophages (right), TLR ligands induce DUSP10 expression that inhibits JNK activity and thereby constrains the production of cytokines and may reduce costimulation of T cells. In T cells (left), DUSP10 is constitutively expressed and inhibits early JNK activation after TCR ligation. Increased JNK activity in the absence of DUSP10 results in reduced proliferation and increased AP-1-dependent production of T cell cytokines. 7502 BRIEF REVIEWS: DUSP MEET IMMUNOLOGY

Ϫ Ϫ TLR and Fc␧R, respectively. In addition, DUSP2 / mast cells genes differentially expressed and regulated in immune cells, failed to proliferate long term, which was due to an increased the modulation and specification of immune receptor initiated rate of apoptosis. In harmony with this impaired responsiveness MAPK signaling by this family of MKP is being revealed in on- Ϫ Ϫ in vitro, DUSP2 / mice were protected in the K/BxN arthritis going biochemical and genetic studies in the mouse model. It is model that particularly depends on the effector functions of likely that phenomena of differential MAPK activation and bi- mast cells and macrophages. ological responses to different stimuli or by different cell types How can this surprising positive effect of DUSP2 be ex- may, at least in part, be attributable to the action of DUSP. For plained at the molecular level? From overexpression studies in example, the findings that the balance between p38 and ERK vitro, DUSP2 appeared to dephosphorylate p38 and ERK (68). activation in DC in response to TLR triggering determines the However, in the absence of DUSP2, a decreased or shortened relative strength of immunosuppressive IL-10 or Th1-driving activation of these MAPK was observed in macrophages and IL-12 production (9, 10) may be explained by regulated expres- Ϫ Ϫ mast cells. A reduced activation of Elk- and AP-1 reporter genes sion patterns of DUSP family members. DUSP1 / macro- showed the functional significance of reduced ERK activation Ϫ Ϫ phageshaveincreasedp38MAPKactivationwhereasERKphos- in DUSP2 / cells. In contrast, JNK activation was increased phorylation is unchanged, but contrary to what might be and the use of JNK inhibitors rescued ERK phosphorylation expected this leads to elevated production of IL-10 but not of and Elk reporter gene activation, suggesting that DUSP2 strengthens ERK activation by blocking JNK. Finally, the au- IL-12 (59, 65). Therefore, the equations that translate expres- sion levels of DUSP and activation states of MAPK into tran- thors also showed that DUSP2 physically interacts with p38, Downloaded from JNK, and ERK, providing a basis for the cross-talk between scriptional responses may not be that simple. There is now a MAPK that is suggested by the data (Fig. 1). Such a negative need to investigate the contribution of individual DUSP to the cross-talk relationship between JNK and the ERK pathway had regulation of the MAPK module in inflammation and infec- been previously described, seemingly dependent on Jun-in- tion, and thereby generate the data necessary to establish these duced gene expression (72). It is worth mentioning that a pos- rules. itive regulatory role for a DUSP in MAPK activation is not http://www.jimmunol.org/ without precedent, as both human DUSP22/JSP-1 and its mu- Impact of DUSP on other signaling pathways? rine orthologue DUSP22/JKAP were found to specifically ac- tivate JNK upon overexpression (73, 74), and murine DUSP22 Another important question for future study is whether and was indeed required for full activation of JNK in response to how DUSP interfere with other signaling pathways, be it indi- TNF-␣ (74). Together, these results are important in demon- rectly via changes in MAPK activity or directly by acting on strating that DUSP proteins not only inhibit biological re- additional substrates. At the moment, there is no evidence for sponses by terminating MAPK activation, but also can deci- direct binding and of non-MAPK targets by sively increase the activation of a specific MAPK. the classical DUSP MKP that contain a MKB domain. This is by guest on September 29, 2021 different for the atypical DUSP that can dephosphorylate a Inclusion of DUSP in the equation: a more accurate description of wide array of target proteins and even RNA. It would therefore MAPK driven immune activation not be too surprising if one or the other of the classical DUSP Recently, the field of research has seen a MKP would also turn out to bind and inactivate novel targets. growing appreciation of the specific and active roles of phos- An indirect impact of the DUSP family is expected for path- phatases in the regulation of physiological processes in general. ways that are already known to cross-talk with the MAPK mod- This shift in attention from kinases to phosphatases was in part ule. For example, p38-dependent histone modifications and due to the realization that mammalian genomes encode a much chromatin remodeling in macrophages and DC after TLR stim- larger number of phosphatases than previously thought. This is ulation facilitates access of NF-␬B transcription factors to the especially true in the case of the MAPK family, where the large promoters of certain cytokines and chemokines (77). We have family of DUSP MKP outnumbers the small group of MAPK. observed that NF-␬B binding sites are overrepresented in the The inclusion of these regulators in the MAPK signaling mod- promoters of DUSP1-contolled LPS-responsive genes, al- ule provides specification and flexibility in the downstream re- though there was no detectable difference in I␬B degradation sponses to MAPK-activating stimuli by introducing a number and nuclear translocation of RelA p65, implying that stronger of additional variables. These include the following: 1) the set of p38 activation in the absence of DUSP1 may increase the re- constitutively expressed DUSP in a given cell that controls the cruitment of NF-␬B transcription factors to the promoters of initial response type; 2) the kinetics of inducible expression of DUSP as feedback inhibitors; 3) subcellular compartmentaliza- these genes (our unpublished data). Serine phosphorylation tion of negative regulation by the action of cytoplasmic and nu- of STAT1 mediated by p38 MAPK represents another example clear DUSP; and 4) DUSP-mediated cross-talk at the level of of cross-talk that may be indirectly controlled by DUSP pro- MAPK that can even result in positive effects on individual teins and contribute to the shaping of the transcriptional re- MAPK. DUSPs belong therefore to a larger group of molecules, sponses (78, 79). Curiously, there are reports from two different including scaffold proteins and other inhibitors, that determine groups suggesting that DUSP1 dephosphorylates STAT1 at ty- the subcellular localization, the intensity and the kinetics of dif- rosine residues in hepatocytes and vascular smooth muscle cells, ferential MAPK activation in different cell types in response to which would imply a more direct interaction with the JAK- various stimuli (75, 76). STAT pathway (80, 81). However, these claims were contested The studies reviewed here demonstrate that DUSP fulfill an by a yeast two hybrid-based investigation of DUSP1 binding important function in innate and adaptive immune cell re- determinants that concluded that direct interactions are limited sponses. Following the identification of different DUSP as to the MAPK family (82). The Journal of Immunology 7503

DUSP as targets for the manipulation of immune responses? 17. Marti, F., A. Krause, N. H. Post, C. Lyddane, B. Dupont, M. Sadelain, and P. D. King. 2001. Negative-feedback regulation of CD28 costimulation by a novel The phenotypic analysis of DUSP-deficient mice has already -activated phosphatase, MKP6. J. Immunol. 166: 197–206. 18. Alonso, A., S. Rahmouni, S. Williams, M. van Stipdonk, L. Jaroszewski, A. Godzik, shown their importance in regulating immune responses in a R. T. Abraham, S. P. Schoenberger, and T. Mustelin. 2003. Tyrosine phosphorylation few models of systemic and local inflammation. These mouse of VHR phosphatase by ZAP-70. Nat. Immunol. 4: 44–48. lines provide ideal tools to investigate the function of DUSP 19. Alonso, A., J. J. Merlo, S. Na, N. Kholod, L. Jaroszewski, A. Kharitonenkov, S. Williams, A. Godzik, J. D. Posada, and T. Mustelin. 2002. 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