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Dual Specificity MAPK Phosphatases in Control of the Inflammatory Response

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Dual Specificity MAPK Phosphatases in Control of the Inflammatory Response DUSP Meet Immunology: Dual Specificity MAPK Phosphatases 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 References This article cites 82 articles, 53 of which you can access for free at: http://www.jimmunol.org/content/177/11/7497.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 29, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. THE 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 genes 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 threonine 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 kinases (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 proteins, 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- gene 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 kinase-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 gene expression 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 phosphatase; 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.
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