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J. Biol. Chem., Vol. 278, Issue 25, 22237-22242, June 20, 2003

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Defining the Involvement of p38 MAPK in the Production of Anti- and Proinflammatory Cytokines Using an SB 203580-resistant Form of the Kinase^*

Xuecui Guo , Robert E. Gerl and John W. Schrader 

From the Biomedical Research Centre, University of British Columbia, 2222 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada

Despite its lack of specificity, the inhibitor SB 203580 has been widely used to implicate p38 mitogen-activated protein kinase (MAPK) in the synthesis of many cytokines. Here we show unequivocally that the production of interleukin (IL)-1, IL-6, IL-10, and tumor necrosis factor (TNF) requires p38 MAPK activity by demonstrating that the inhibitory effects of SB 203580 were reversed by expression of an SB 203580-resistant form of p38 (SBR-p38) that fails to bind to SB 203580. This strategy established the requirement for p38 activity for the lipopolysaccharide-stimulated production of IL-10, IL-1, and IL-6 by the monocytic cell WEHI 274 and the production of IL-6 and TNF stimulated by ligation of the Fc- receptor of the mast cell MC/9. Expression of SBR-p38 in primary macrophages abrogated the ability of SB 203580 to inhibit the lipopolysaccharide-stimulated production of TNF but not of IL-10. Expression of SBR-p38 in primary T lymphocytes abrogated the ability of SB 203580 to inhibit the production of interferon- induced by co-ligation of CD3 and CD28 but not the production of interferon- or IL-10 induced by IL-12. These results suggest that the levels of p38 MAPK activity required for maximal cytokine production vary with different cytokines and stimuli.

Received for publication, January 27, 2003

^* This project was supported by the Canadian Institutes of Heath Research and The Arthritis Society of Canada. 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.

A trainee of the Canadian Arthritis Networks.

To whom correspondence should be addressed. Tel.: 604-822-7822; Fax: 604-822-7815; E-mail: john{at}brc.ubc.ca.

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