Chemical genetics define the roles of p38alpha and p38beta in acute and chronic inflammation.
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.
O'Keefe
Stephen J
SJ
Department of Immunology, Merck Research Laboratories, Rahway, New Jersey 07065, USA. stephen_okeefe@merck.com
Mudgett
John S
JS
Cupo
Susan
S
Parsons
Janey N
JN
Chartrain
Nicole A
NA
Fitzgerald
Catherine
C
Chen
Shiow-Ling
SL
Lowitz
Karen
K
Rasa
Cordelia
C
Visco
Denise
D
Luell
Silvi
S
Carballo-Jane
Ester
E
Owens
Karen
K
Zaller
Dennis M
DM
D000208:Acute Disease; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D002908:Chronic Disease; D003001:Cloning, Molecular; D003094:Collagen / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D007249:Inflammation; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D048290:Mitogen-Activated Protein Kinase 11 / Q000378:metabolism*; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism*; D017354:Point Mutation; D020033:Protein Isoforms
D000911:Antibodies, Monoclonal; D020033:Protein Isoforms; D003094:Collagen; D048290:Mitogen-Activated Protein Kinase 11; D048308:Mitogen-Activated Protein Kinase 14