Abstract
Since 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.
Highlights
The mitogen-activated protein kinase (MAPK) family comprises at least four groups, namely p38, extracellular signal-related kinases 1 and 2 (ERK1 and ERK2), Jun aminoterminal kinases (JNKs), and ERK5
We have recently shown that p38 MAPK does not control IFN-γ expression induced by T cell receptor (TCR) and CD28 stimulation in human T cells, a moderate and transient reduction of IFN-γ expression occurred after inhibition of p38 MAPK in the presence of IL-12, indicating that the p38 MAPK pathway is involved in mediating IL-12-induced IFN-γ expression [60]
We have recently shown that in human memory CD4 T cells, stabilization of IL-4 and IL-13 mRNA by CD28 stimulation is mediated by p38 MAPK [60]
Summary
The mitogen-activated protein kinase (MAPK) family comprises at least four groups, namely p38, extracellular signal-related kinases 1 and 2 (ERK1 and ERK2), Jun aminoterminal kinases (JNKs), and ERK5. In human CD4 T cells, inhibition of p38 MAPK by SB203580 or by a dominant-negative mutant of p38 MAPK reduced the expression of IL-4, IL-5, and IL-13 in response to CD3 and/or CD28 stimulation [60,61], indicating that the p38 MAPK pathway has a critical role in the regulation of Th2 cytokine expression in primary human T cells (Fig. 2). Because of its essential role in TNF and IFN-γ expression by macrophages and T cells, respectively, the p38 MAPK signaling cascade is considered a promising therapeutic target for Th1-mediated inflammatory diseases [103]. A different p38 MAPK inhibitor, VX-702, was shown to reduce serum C-reactive protein levels in patients with acute coronary syndrome [113] These data suggest that in humans, p38 MAPK activation is essential in acute inflammatory processes such as sepsis or acute coronary syndrome, but its precise function in chronic inflammatory processes such as those mediating autoimmune diseases remains unclear. Targeting downstream molecules of p38 MAPK or the development of nonATP-competitive inhibitors of p38 MAPK may be attractive alternative approaches to the therapeutic disruption of p38 MAPK-mediated effects [118]
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