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J. Biol. Chem., Vol. 282, Issue 48, 34663-34671, November 30, 2007

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Chemical Genetics Define the Roles of p38 and p38β in Acute and Chronic Inflammation^*

Stephen J. O'Keefe¹, John S. Mudgett, Susan Cupo, Janey N. Parsons, Nicole A. Chartrain, Catherine Fitzgerald, Shiow-Ling Chen, Karen Lowitz^¶, Cordelia Rasa^¶, Denise Visco^¶, Silvi Luell^||, Ester Carballo-Jane^||, Karen Owens^**, and Dennis M. Zaller

From the Department of Immunology, the Center for Genetically Engineered Models, and the Departments of ^¶Laboratory Animal Research, ^||Pharmacology, and ^**Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065

The p38 MAP kinase signal transduction pathway is an important regulator of proinflammatory cytokine production and inflammation. Defining the roles of the various p38 family members, specifically p38 and p38β, in these processes has been difficult. Here we use a chemical genetics approach using knock-in mice in which either p38 or p38β kinase has been rendered resistant to the effects of specific inhibitors along with p38β knock-out mice to dissect the biological function of these specific kinase isoforms. Mice harboring a T106M mutation in p38 are resistant to pharmacological inhibition of LPS-induced TNF production and collagen antibody-induced arthritis, indicating that p38β activity is not required for acute or chronic inflammatory responses. LPS-induced TNF production, however, is still completely sensitive to p38 inhibitors in mice with a T106M point mutation in p38β. Similarly, p38β knock-out mice respond normally to inflammatory stimuli. These results demonstrate conclusively that specific inhibition of the p38 isoform is necessary and sufficient for anti-inflammatory efficacy in vivo.

Received for publication, May 23, 2007 , and in revised form, August 22, 2007.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Immunology, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065. Fax: 732-594-7177; E-mail: stephen_okeefe{at}merck.com.

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