ReviewInhibition of p38 MAP kinase as a therapeutic strategy
Section snippets
p38 MAP kinase homologs
As is the case with both ERKs and JNKs, multiple members of the p38 MAP kinase family have been identified (Cobb and Goldsmith, 1995). Murine p38 was first identified as a kinase activated in response to bacterial LPS (Han et al., 1994). Soon after, human CSBP1 and CSBP2/p38 were identified as targets of a class of pyridinylimidazole compounds that inhibited the production of inflammatory cytokines from activated monocyte/macrophages (Lee et al., 1994). CSBP1 and CSBP2 differ from each other by
Substrates
A number of substrates of p38 MAP kinase have been identified. These include other kinases such as MAPKAP K2/3, p38-regulated/activated protein kinase (PRAK), MAP kinase-interacting kinase 1 and 2 (MNK1/2), mitogen and stress-activated kinase 1 (MSK1)/RLPK, and ribosomal S6 kinase-B (RSK-B); transcription factors such as activation transcription factors 2 and 6 (ATF2/6), myocyte enhancer factor 2C (MEF2C), C/EBP homologous protein (CHOP), Elk1 and SAP-1A and cytosolic proteins such as stathmin.
Signaling pathways involving p38 MAP kinase
Significant progress has been made in defining the exact molecular pathways of p38 MAP kinase activation and subsequent signaling. Members of the p38 MAP kinase family are phosphorylated on Thr and Tyr residues in a Thr-Gly-Tyr motif by a dual specificity MKK. Initially, it was thought that among upstream MKKs, MKK 3, 4 and 6 all activated p38 MAP kinase Derijard et al., 1995, Han et al., 1996, Raingeaud et al., 1996. However, recent data suggest that MKK6 and, under certain conditions, MKK3
Role of p38 MAP kinase in cytokine production and function
The role of p38 MAP kinase in the regulation of cytokine production or function was not appreciated until the discovery of p38 MAP kinase activation in LPS stimulated macrophages (Han et al., 1994) and the simultaneous identification of the molecular target of compounds previously shown to inhibit cytokine biosynthesis (Lee et al., 1994). It is now known that the regulation of cytokine biosynthesis in many different cell types is regulated through activation of p38 MAP kinase Beyaert et al.,
p38 MAP kinase and hematopoietic cells
In murine T-cells, the p38 MAP kinase inhibitor, SB 203580 inhibited the production of interferon-gamma by Th1 cells without affecting IL-4 production by Th2 cells (Rincon et al., 1998). Overexpression of dominant-negative p38 MAP kinase results in selective impairment of Th1 responses whereas constitutively activated MKK6 overexpression caused increased production of interferon-gamma. In another study, it was shown that SB 203580 inhibited CD28-dependent T-cell proliferation and IL-2 in vitro
Inflammatory diseases
The widely used p38 MAP kinase inhibitor, SB 203580, has been profiled in a number of models in vivo and demonstrated its activity in a wide variety of TNF alpha mediated disease models (Badger et al., 1996). The compound inhibited LPS-induced TNF production with IC50 of 15 and 25 mg/kg in mice and rats, respectively. It was effective in reducing paw inflammation in the adjuvant arthritic rat with optimum inhibition observed at 60 mg/kg. There is also evidence for protection of joint integrity
Compounds
The bicylic pyridinylimidazole SKF 86002 was first reported to inhibit LPS-stimulated cytokine production Lee et al., 1988, Lee et al., 1993, Lee et al., 1994, Lee et al., 1999. In 1993, the SAR for inhibition of cytokine synthesis by bicyclic imidazoles was described in a publication which explored dual 5-LO/COX and cytokine inhibition as potential mechanisms for the potent anti-inflammatory activity of these compounds (Lee et al., 1993). Subsequently, SB 203580, and other 2,4,5-triaryl
Conclusion and perspectives
Our increased understanding of the signal transduction pathways involved in the regulation of cytokine production and cytokine signaling in immune cells has opened the door for the discovery of novel therapeutics useful in treating a variety of inflammatory diseases in which cytokine production or signaling is implicated. The availability of potent and selective inhibitors of such signaling pathways also provide a means to further dissect the pathways to increase our understanding of the
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