The role of p38 mitogen-activated protein kinase in primary human T cells is incompletely understood. We analyzed in detail the role of p38 in the regulation of effector functions and differentiation of human CD4 T cells by using a p38-specific inhibitor and a dominant-negative mutant of p38. p38 was found to mediate expression of IL-10 and the Th2 cytokines IL-4, IL-5, and IL-13 in both, primary naive and memory T cells. In contrast, inhibition of p38 activity did not affect expression of the Th1 cytokines IFN-c and TNF induced by TCR-stimulation, but decreased IL-12-mediated IFN-c expression. Cytokine expression from established Th2 effector cells was also regulated by p38, however, the role of p38 was less pronounced compared to primary CD4 T cells. p38 MAPK regulated cytokine gene expression at both, the transcriptional level by activating gene transcription and the post-transcriptional level by stabilizing cytokine mRNA. As a result of the effect of p38 on IL-4 expression, p38 activity modulated differentiation of naive precursor T cells by inducing a shift of the Th1/Th2 balance toward the immuno-modulatory Th2 direction. Together, the data suggest that p38 plays a key role in human Th2 cell immune responses.

Inflammatory cytokines like TNF play a central role in autoimmune disorders such as rheumatoid arthritis. We identified the tyrosine kinase bone marrow kinase on chromosome X (BMX) as an essential component of a shared inflammatory signaling pathway. Transient depletion of BMX strongly reduced secretion of IL-8 in cell lines and primary human cells stimulated by TNF, IL-1β, or TLR agonists. BMX was required for phosphorylation of p38 MAPK and JNK, as well as activation of NF-κB. The following epistasis analysis indicated that BMX acts downstream of or at the same level as the complex TGF-β activated kinase 1 (TAK1)–TAK1 binding protein. At the cellular level, regulation of the IL-8 promoter required the pleckstrin homology domain of BMX, which could be replaced by an ectopic myristylation signal, indicating a requirement for BMX membrane association. In addition, activation of the IL-8 promoter by in vitro BMX overexpression required its catalytic activity. Genetic ablation of BMX conferred protection in the mouse arthritis model of passive K/BxN serum transfer, confirming that BMX is an essential mediator of inflammation in vivo. However, genetic replacement with a catalytically inactive BMX allele was not protective in the same arthritis animal model. We conclude that BMX is an essential component of inflammatory cytokine signaling and that catalytic, as well as noncatalytic functions of BMX are involved.

The intracellular signaling pathway by which tumor necrosis factor (TNF) induces its pleiotropic actions is well characterized and includes unique components as well as modules shared with other signaling pathways. In addition to the currently known key effectors, further molecules may however modulate the biological response to TNF. In our attempt to characterize novel regulators of the TNF signaling cascade, we have identified transmembrane protein 9B (TMEM9B, c11orf15) as an important component of TNF signaling and a module shared with the interleukin 1␤ (IL-1␤) and Toll-like receptor (TLR) pathways. TMEM9B is a glycosylated protein localized in membranes of the lysosome and partially in early endosomes. The expression of TMEM9B is required for the production of proinflammatory cytokines induced by TNF, IL-1␤, and TLR ligands but not for apoptotic cell death triggered by TNF or Fas ligand. TMEM9B is essential in TNF activation of both the NF-B and MAPK pathways. It acts downstream of RIP1 and upstream of the MAPK and IB kinases at the level of the TAK1 complex. These findings indicate that TMEM9B is a key component of inflammatory signaling pathways and suggest that endosomal or lysosomal compartments regulate these pathways. Tumor necrosis factor (TNF)2 is a pleiotropic mediator of a wide range of cellular responses to infection, such as cytokine and chemokine production, cell migration, cell death, and cell differentiation and maturation (1). TNF plays a pivotal role in several autoimmune disorders such as rheumatoid arthritis; this is underscored by the clinical success of neutralizing TNF with antibodies or soluble receptors (2). A better understanding of intracellular TNF signaling is therefore of high clinical relevance.The two TNF receptors, TNFR1 (p55, TNFRSF1A) and TNFR2 (p75, TNFRSF1B), show high homology in their extracellular domains but less in their intracellular domains. Although soluble TNF binds TNFR1 with higher affinity than TNFR2 and therefore acts primarily via TNFR1, membranebound TNF activates equally TNFR1 and TNFR2 (3). In most tissues TNF signaling is mediated by TNFR1, whereas TNFR2 is restricted to fewer specific tissues, mostly of an immunological nature (3). Upon ligand binding, TNFR1 trimerizes and recruits TNF receptor-associated death domain protein (TRADD), receptor-interacting protein 1 (RIP1), and TNF receptor-associated factor 2 (TRAF2). This first complex acts as a platform at the plasma membrane to activate the NF-B and MAPK signaling cascades, promoting cell survival and the expression of inflammatory cytokines. In a second step, TNFR1 is internalized into endocytic vesicles together with TRADD and RIP1 and recruits the proapoptotic molecules Fas-associated death domain (FADD) and caspase-8. This complex will initiate the apoptotic cell death program if concurrent anti-apoptotic NF-B activation is absent (4).The TGF␤-activated kinase 1 (TAK1) complex has a central function in many inflammatory pathways such as the TNFR, interleukin 1␤ receptor (IL-1R), and several Toll-...

APC = antigen-presenting cell; ARE = AU-rich element; CaMK = calcium/calmodulin-dependent protein kinase; COX = cyclo-oxygenase; CREB = cAMP-response element-binding protein; ERK = extracellular signal-related kinase; GADD = growth arrest and DNA damage-inducible genes; GEF = guanine nucleotide exchange factor; IFN = interferon; IL = interleukin; JNK = c-Jun amino-terminal kinase; LAT = linker for activation of T cells; LPS = lipopolysaccharide; MAPK = mitogen-activated protein kinase; MHC = major histocompatibility complex; MIP = macrophage inflammatory protein; MK = MAP kinase-activated protein kinase; MKK = MAPK kinase; MKKK = MAPK kinase kinase; MSK = mitogen-and stress-activated kinase; NFAT = nuclear factor of activated T cells; NF-κB = nuclear factor κB; Pak1 = p21-activated kinase 1; STAT = signal transducer and activator of transcription; TCR = T cell receptor; Th = T helper; TNF = tumor necrosis factor; TTP = tristetraprolin. Available online http://arthritis-research.com/content/8/2/205 AbstractSince the identification of the p38 mitogen-activated protein kinase (MAPK) as a key signal-transducing molecule in the expression of the proinflammatory cytokine tumor necrosis factor (TNF) more than 10 years ago, huge efforts have been made to develop inhibitors of p38 MAPK with the intent to modulate unwanted TNF activity in diseases such as autoimmune diseases or sepsis. However, despite some anti-inflammatory effects in animal models, no p38 MAPK inhibitor has yet demonstrated clinical efficacy in human autoimmune disorders. One possible reason for this paradox might relate to the fact that the p38 MAPK signaling cascade is involved in the functional regulation of several different cell types that all contribute to the complex pathogenesis of human autoimmune diseases. In particular, p38 MAPK has a multifaceted role in CD4 T cells that have been implicated in initiating and driving sustained inflammation in autoimmune diseases, such as rheumatoid arthritis or systemic vasculitis. Here we review recent advances in the understanding of the role of the p38 MAPK signaling cascade in CD4 T cells and the consequences that its inhibition provokes in T cell functions in vitro and in vivo. These new data suggest that p38 MAPK inhibitors may elicit several unwanted effects in human autoimmune diseases but may be useful for the treatment of allergic disorders.

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