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 p38alpha and p38beta, in these 
processes has been difficult. Here we use a chemical genetics approach using 
knock-in mice in which either p38alpha or p38beta kinase has been rendered 
resistant to the effects of specific inhibitors along with p38beta knock-out 
mice to dissect the biological function of these specific kinase isoforms. Mice 
harboring a T106M mutation in p38alpha are resistant to pharmacological 
inhibition of LPS-induced TNF production and collagen antibody-induced 
arthritis, indicating that p38beta 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 p38beta. 
Similarly, p38beta knock-out mice respond normally to inflammatory stimuli. 
These results demonstrate conclusively that specific inhibition of the p38alpha 
isoform is necessary and sufficient for anti-inflammatory efficacy in vivo.