A review on the recent advances in the understanding of the role …

• Abstract
• Introduction
• The p38 MAPK signaling cascade
• Regulation of cytokine expression by p38 MAPK in CD4 T cells
• Conclusion and perspectives
• References
• Figures
• Table

Biology Articles » Biochemistry » The p38 mitogen-activated protein kinase signaling cascade in CD4 T cells » Conclusion and perspectives

Conclusion and perspectives

- The p38 mitogen-activated protein kinase signaling cascade in CD4 T cells

The characterization of p38 MAPK as a key player in inflammation more than 10 years ago led to the development of several p38 MAPK inhibitors for the treatment of inflammatory autoimmune diseases. Although these inhibitors were potent in animal models of autoimmune diseases and in human acute inflammatory disorders, several clinical trials with p38 MAPK inhibitors have been discontinued because of serious side effects, in particular at the level of the central nervous system. New p38 MAPK inhibitors that are unable to cross the blood-brain barrier are now in clinical trials in rheumatoid arthritis and will delineate precisely the role of p38 MAPK in Th1-driven chronic inflammatory diseases. However, in view of recent advances underlining the essential role of p38 MAPK in IL-10 expression and in Th2 cell functions and of the regulatory capacities of IL-10 and Th2 cells in Th1-driven inflammation, p38 MAPK inhibitors might be associated with some unwanted effects on the immune system, enhancing rather than ameliorating the underlying inflammatory response in Th1-driven diseases. In contrast, these inhibitors may be useful as therapy in Th2-driven inflammatory disorders. However, as p38 MAPK also has essential functions in other organ systems beside the immune system, it may be necessary to characterize precisely the signal cascades downstream of p38 MAPK that control effector functions in the immune system to identify those that are involved in unwanted immune responses without interfering with essential physiologic functions of the p38 MAPK signaling cascade in other organ systems. This might provide therapeutic targets to specifically block, for example, TNF production by macrophages in autoimmune diseases or Th2 effector functions in allergic disorders.


Abbreviations


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.


Competing interests


The author(s) declare that they have no competing interests.


Acknowledgements


The authors thank Professor PE Lipsky for a critical reading of the manuscript and for fruitful discussions. The work was supported in part by the Deutsche Forschungsgemeinschaft (grants Schu 786/2–3 and 2–4) and by the Interdisciplinary Center for Clinical Research (IZKF) at the University hospital of the University of Erlangen-Nuremberg (projects B27 and B3).