Inflammation-activated protein kinases as targets for drug development.
Given the prevalence and debilitating nature of chronic inflammatory diseases, there is a never-ending quest to identify novel targets for the rational development of antiinflammatory drugs. The major signaling pathway that controls inflammation-associated gene expression is the one which leads to activation of transcription factor nuclear factor-kappaB. Therefore, inhibitors of the kinase responsible for nuclear factor-kappaB activation, IkappaB kinase, are expected to have potent antiinflammatory activity. Indeed, our results with cell type-specific inactivation of the beta-catalytic subunit of IkappaB kinase are by and large consistent with this assertion. In addition to IkappaB kinase and nuclear factor-kappaB, the expression of certain proinflammatory cytokines, such as interleukin-1 and tumor necrosis factor-alpha, is dependent on mitogen-activated protein kinases. Therefore, considerable attention has also been given to mitogen-activated protein kinases as likely targets for the development of novel antiinflammatory therapeutics. Preliminary preclinical data suggest that inhibitors that target all these pathways exhibit antiinflammatory activity. This review focuses on the possible mechanisms through which such inhibitors may interfere with inflammation and some of the complications that may be associated with their use.
Karin
Michael
M
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0723, USA. karinoffice@ucsd.edu
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D015533:Transcriptional Activation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D016328:NF-kappa B; D051550:I-kappa B Kinase; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4