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Cytokine synthesis and inflammatory mediator release (PGE2,iNOS)

Fig. 1 p38 MAPK pathways with activators and substrates were described. These kinases exhibit between 60% and 70% amino acid identity to one another. Differences have been demonstrated in the sequence and size of their activation loop as well as their responsiveness to different stimuli. Each of the MAPK sub-families has been shown to consist of multiple isoforms and sub-family members. Activation of the kinases occurs through the dual phosphorylation of Thr and Tyr residues in a "TXY" motif (X being Glu, Pro or Gly in ERKs, JNKs and p38 respectively) by a dual specificity MAPKK (Pearson et al. 2001). A serine threonine kinase, MAP-KKK, is responsible for the phosphorylation of MAPKK. As previously stated, the MAPK can be differentiated by their responsiveness to stimuli. In general, the ERKs have been shown to respond to mitogenic and prolifera-tive stimuli, whereas the JNKs and p38 MAPKs respond to environmental stresses such as UV light, heat, osmotic shock and exposure to inflammatory cytokines (Pearson et al. 2001).

The elucidation of the p38 MAPK pathway began almost a decade ago, when the murine p38 was identified as a major phosphoprotein activated as a result of bacterial lipopolysaccharide (LPS) challenge (Han et al. 1994). Shortly following this discovery, human p38 was identified as the molecular target for members of the pyridinylimidazole class of compounds which were known to inhibit the biosynthesis of inflammatory cytokines in LPS-stimu-lated human monocytes (Lee et al. 1994). The extensive use of bioinformatics has led to the identification p38b2, p38g, and p38d. Of the four isoforms of human p38 so far described, p38a is both the best characterized and potentially the most relevant in its involvement in the inflammatory response. Tissue distribution data for p38a and @2 demonstrate them to be widely expressed across a variety of tissues. Functionally, however, they appear to be distinct. For example, while both p38a and p38b2 were shown to be elevated in a mouse model of ventricular hypertrophy, increased p38a activity was associated with cardiomyocyte apoptosis, whereas elevated p38b2 led to an induction of cardiomyocyte hypertrophy (Braz et al. 2003). Much less is known about the functional role of the other two kinases, p38g and d. A wide tissue distribution in both adult and developing tissues has been shown for p38d, whereas p38g showed a more restricted distribution in skeletal muscle. A possible role for p38g in cardiac pathophysiology has recently been postulated with the discovery of its expression in normal and diseased human heart tissue and in normal and hypertrophic rat myocytes (Court et al. 2002).

Activation of p38a and @2 MAPK occurs through the dual phosphorylation of Thr180 and Tyr182 by the upstream MAPKK, MKK6. Another MAPKK, MKK3 has also been shown to activate p38a MAPK. MKK3/6 are, in turn, activated by several MAPKKK in response to a variety of stimuli (Adams et al. 2001a; Kyriakis and Avruch 2001) (Fig. 1). These multiple activation pathways serve to illustrate the complexity of this cascade. Recently, a MAPKK-independent pathway of p38a MAPK activation has been described. This involves the transforming growth factor-b-activated protein kinase-1

(TAK-1) binding protein 1, TAB1 (Ge et al. 2002). Using a yeast two-hybrid system, TAB1 was shown to associate with p38a and induce its intramolecular autophosphorylation. The substrates of the p38 MAPK include other kinases, transcription factors, and cytosolic proteins. Various protein phosphatases including protein phosphatase 2A have been shown to dephosphorylate p38 MAPK, resulting in its downregulation. p38a MAPK is also downregulat-ed through the dephosphorylation activity of MAPK phosphatase (MKP)-7 and MKP-5 (Theodosiou et al. 1999; Masuda et al. 2001; Tanoue et al. 2001).

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