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The Proceedings of the American Thoracic Society 2:386-390 (2005)
© 2005 The American Thoracic Society

Inflammation-activated Protein Kinases as Targets for Drug Development

Michael Karin

Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California, San Diego School of Medicine, San Diego, California

Correspondence and requests for reprints should be addressed to Michael Karin, Ph.D., 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. E-mail: karinoffice{at}ucsd.edu

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-{kappa}B. Therefore, inhibitors of the kinase responsible for nuclear factor-{kappa}B activation, I{kappa}B kinase, are expected to have potent antiinflammatory activity. Indeed, our results with cell type–specific inactivation of the ß-catalytic subunit of I{kappa}B kinase are by and large consistent with this assertion. In addition to I{kappa}B kinase and nuclear factor-{kappa}B, 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.

Key Words: antiinflammatory drugs • extracellular signal–regulated kinase • I{kappa}B kinase • Jun-N terminal kinase • p38 mitogen–activated protein kinase




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