p38 MAPK is a serine/threonine kinase which was originally isolated from lipopolysaccharide (LPS) stimulated monocytes. It is a key member of the MAPK family and a central component in the p38 signaling pathway. The p38 signaling pathway is rapidly activated by topoisomerase II and histone deacetylase inhibitors, osmotic shock, microtubule disassembly and UV light. The p38 pathway was traditionally associated with the stress and immune responses but more recently it has been shown to be involved in apoptosis and cell differentiation (1). The p38 pathway can also regulate cellular growth and cell cycle checkpoints in different ways, depending on the cell type and the stimulus (2).

Diverse stimuli activate the p38 signaling pathway by stimulating membrane proximal components such as MEKKs, ASK1, TAK1/TAB1 or MLK3 which in turn phosphorylate and activate MKK3/6 and MKK4. The MKK3/6 and MKK4 are termed the p38 MAPK kinases and they mediate the activation of the p38 MAPK family members (3). p38 MAPK is involved in the regulation of HSP27, MAPKAPK2, MAPKAPK3, MNK1/2 and a variety of transcription factors including ATF-2, Stat1, MEF2 and Elk1.

p38 MAPKs represents a point of convergence for multiple signaling processes that are activated in inflammation and thus a key potential target for the modulation of cytokine production. Specific inhibitors of p38 MAPK block production of the major inflammatory cytokines (i.e. TNFa and IL-1) and other proteins (e.g. COX-2), and are anti-inflammatory in animal models of disease (4). A major function of the p38 MAPK pathway is posttranscriptional control of inflammatory gene expression.

Over the last few years, there have been multiple reports of cytokine suppression in humans following oral administration of p38 MAPK inhibitors. These results, in addition to proof of concept studies in rheumatoid patients, have established p38 MAPK inhibition as an avenue for the future management of pro-inflammatory cytokine based diseases (5). At present, at least seventeen p38 MAPK inhibitors have successfully advanced into clinical testing (6).

REFERENCES
1. Zarubin, T. et al: Activation and signaling of the p38 MAP kinase pathway. Cell Res. 2005 Jan;15(1):11-8.
2. Pearce, A. K. et al: Integrating stress-response and cell-cycle checkpoint pathways. Trends Cell Biol. 2001 Oct;11(10):426-33.
3. Wang, W. et al: Sequential activation of the MEK-extracellular signal-regulated kinase and MKK3/6-p38 mitogen-activated protein kinase pathways mediates oncogenic ras-induced premature senescence. Mol Cell Biol. 2002 May;22(10):3389-403.
4. Saklatvala, J.: The p38 MAP kinase pathway as a therapeutic target in inflammatory disease. Curr Opin Pharmacol. 2004 Aug;4(4):372-7.
5. Westra, J. et al: p38 mitogen-activated protein kinase (MAPK) in rheumatoid arthritis. Mini Rev Med Chem. 2006 Aug;6(8):867-74.
6. Lee, M. R. et al: MAP kinase p38 inhibitors: Clinical results and an intimate look at their interactions with p38alpha protein. Curr Med Chem. 2005;12(25):2979-94.