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 amino-terminal kinases (JNKs), and ERK5. Within this family, the p38 MAPK was characterized in 1994 by Han et al. as a protein kinase that was tyrosine phosphorylated in mammalian cells in response to lipopolysaccharide (LPS) and extracellular changes in osmolarity, linking the p38 MAPK signaling pathway to stress-induced responses [1]. The p38 MAPK became an interesting therapeutic target in inflammatory diseases because in the same year Lee et al. [2] showed that the p38 MAPK has a pivotal role in mediating tumor necrosis factor (TNF) production by macrophages in response to stimulation with LPS. Since then, many different inhibitors have been developed that have greatly facilitated the definition of the role of p38 MAPK in many biologic systems. By using these inhibitors in combination with transgenic mice expressing constitutively active or inactive forms of p38 MAPK, p38 MAPK was shown to be involved in many cellular responses in mammalian cells including cell cycle regulation [3], cell death [4], cell development, and cell differentiation [5]. In the immune system, the p38 MAPK signaling cascade has been implicated in the regulation of innate immunity, for example by mediating endotoxin-induced TNF expression, and also in the regulation of adaptive immunity, for example by controlling T cell activation and differentiation [5].
Antigen-presenting cells (APCs) activate CD4 T cells by presenting their specific antigen in the context of appropriate major histocompatibility complex (MHC) class II molecules. The antigen is recognized by T cells by means of their antigen-specific T cell receptor (TCR). In addition to the MHC-TCR contact, APCs and T cells communicate through co-stimulatory molecules, such as CD80 and CD86 expressed by APCs and their ligand, CD28 expressed by T cells, and through cytokines. Once activated, CD4 T cells proliferate and differentiate into two main subsets of primary effector cells, T helper type 1 (Th1) or Th2 cells, characterized by their specific cytokine expression pattern [6]. Th1 cells promote cellular immunity and macrophage activation largely through the production of their signature proinflammatory cytokine IFN-γ. They control immune responses against microbial infections and intracellular parasites and are involved in the development of autoimmune inflammatory diseases such as rheumatoid arthritis [7,8]. Th2 cells, through the expression of IL-4, IL-5, and IL-13, induce IgE production by B cells and eosinophil-mediated and mast-cell-mediated immune responses, and orchestrate the defense against extracellular parasites [9]. Th2 cells have a central role in driving the immune response in asthma and atopic diseases [10]. In addition, Th2 cells, through the production of IL-4, downmodulate Th1 differentiation and macrophage activation and may have regulatory capacities for Th1-mediated inflammation [11]. The Th1/Th2 balance is therefore considered to be pivotal in chronic inflammatory diseases, such as rheumatoid arthritis, in which excessive Th1 inflammation may be a consequence of impaired Th2 differentiation [12]. The nature of a T cell response, namely a Th1 or Th2 response, is modulated by the strength of the MHC-TCR contact, the nature of the co-stimulatory signals, and the nature of the cytokine environment during T cell priming [13]. Integration of these different extracellular signals within T cells is accomplished by several signaling cascades, including the p38 MAPK pathway. Indeed, disruption of the p38 MAPK signaling cascade can affect T cell differentiation as well as T cell effector functions.
In addition to T cells, macrophages also have an essential role in autoimmune disorders, for example through the production of the proinflammatory cytokines TNF and IL-1. Because the p38 MAPK signaling cascade has been implicated in TNF expression, p38 MAPK is considered to be a potential therapeutic target for inflammatory disorders such as autoimmune diseases, and several p38 MAPK inhibitors are currently in clinical trials. However, because T cells and macrophages both are involved in autoimmune inflammation and because the function of both is regulated by the p38 MAPK signaling cascade, understanding the function of p38 MAPK in human T cells may be extremely valuable with regard to clinical applications of p38 MAPK inhibitors.
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