Menu Close

MKP-1 is necessary for T cell activation and function

MKP-1 is necessary for T cell activation and function. production of chemokines and decreased infiltration of the target tissue by immune cells. p38 linked IL-17 receptor (IL-17R) signaling to the expression of genes encoding proinflammatory chemokines and cytokines. Mice that lacked MAPK phosphatase 1 (MKP-1), an inhibitor of p38, had exacerbated EAE and enhanced expression of IL-17RCdependent genes. Our results suggest that the p38CMKP-1 signaling axis links IL-17R signaling in tissue-resident cells to autoimmune inflammation dependent on infiltrating TH17 cells. Introduction Immune dysregulation is the cause of human autoimmune disorders. Multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS), results from uncontrolled autoreactive T cells that infiltrate Penthiopyrad the CNS and attack the myelin sheath (1, 2). In particular, T helper 17 (TH17) cells, a subset of CD4+ effector T cells that secrete the proinflammatory cytokine interleukin-17 (IL-17), play a key pathogenic role in MS (3). In experimental autoimmune encephalomyelitis (EAE), the principal animal model used to study the neuroinflammatory events associated with MS (4), autoimmune inflammation occurs in a multi-step process, which includes both the induction and effector phases. Myelin-reactive CD4+ T cells are activated in the periphery and then enter the perivascular space of the CNS, in which they re-encounter myelin antigens presented by local antigen-presenting cells (APCs). After reactivation, these T cells invade the CNS parenchyma, recognize antigens on myelinated axons, and release IL-17, granulocyte macrophage colony-stimulating factor (GM-CSF), and other proinflammatory molecules, which in turn stimulate CNS-resident cells to activate an inflammatory cascade. Therefore, a complex inflammatory reaction involving both the adaptive and innate immune systems governs disease progression. The differentiation of TH17 cells is usually orchestrated by polarizing cytokines, including IL-1, IL-6, transforming growth factor- (TGF-), and IL-23, which are mainly produced by APCs, especially dendritic Penthiopyrad cells (DCs) (3). Studies have revealed an intricate network of molecular pathways that program the differentiation of TH17 cells. At the transcriptional level, TH17 cell differentiation requires the function of a set of transcription factors, including RAR-related orphan receptor (ROR), RORt, interferon regulatory factor 4 (IRF4), signal transducer and activator of transcription 3 (STAT3), and runt-related transcription factor 1 (RUNX1) (3). In contrast to our extensive knowledge of the T cellCintrinsic pathways that are required for IL-17 production, there has been far less emphasis on how TH17 cells mediate the inflammation of target tissues at the molecular level. Available evidence suggests that both IL-17 and GM-CSF produced by TH17 cells contribute to the encephalitogenic program (5-8). IL-17 and IL-17 receptors (IL-17Rs) are the founding members of a particular subclass of cytokines and receptors that exhibit signaling properties distinct from those of the better-defined cytokines and their receptors, such as the tumor necrosis factor receptor (TNFR), IL-1R, and IL-12R families (9). Although studies have identified the pathogenic functions of IL-17Rs (10) and the IL-17R signaling adaptor molecule Act1 (11, 12), how TH17 cells participate in EAE pathogenesis and, in particular, how IL-17R signals are transduced by an intracellular signaling network in target cells, remain unresolved. Mitogen-activated protein kinases (MAPKs), which include extracellular signalCregulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38, constitute fundamental pathways for cellular responses to a wide range of inflammatory signals (13). In particular, p38 MAPK is usually by far the most extensively investigated protein kinase target for the development of anti-inflammatory drugs in the pharmaceutical industry, because of its potent role in inflammation and the availability of a large array of pharmacological inhibitors (14); however, the nonspecific Penthiopyrad effects inherent in pharmacological approaches make them unlikely to provide definitive mechanistic insights (15, 16). Of note, p38 inhibitors interfere with the functions of important immune regulators, such as receptor-interacting protein 2 (RIP2) (17) and the AktCmechanistic target of rapamycin (mTOR) pathway (18). From this perspective, genetic dissection of signaling pathways has been MAPKK1 highly instrumental in our understanding of the specific functions of MAPKs in immune cells (13, 19). For example, we and others established a key role for p38 in DCs in mediating the crosstalk between innate and adaptive immunity for the induction of TH17 cell differentiation, as well as for the pathogenesis of autoimmune disorders (20, 21). Conversely, MAPK phosphatase 1 (MKP-1), a potent inhibitor of p38 and other MAPKs (22), suppresses the DCCdependent differentiation of TH17 cells (23). Moreover, p38 exerts both pro- and anti-inflammatory activities in a cell contextCdependent manner (24, 25). These effects contribute to the variable effects observed in the preclinical and clinical targeting of p38, and reinforce the importance of genetic dissection of p38 functions in vivo. Despite these advances in our understanding of the physiological functions of p38 in immune.