Chemical genetics define the roles of p38α and p38β in acute and chronic inflammation

Abstract

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 p38α and p38β, in these processes has been difficult. Here we use a chemical genetics approach using knock-in mice in which either p38α 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 p38α 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 p38α isoform is necessary and sufficient for anti-inflammatory efficacy in vivo. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.