A specific inhibitor of the p38 mitogen activated protein kinase affects differentially the production of various cytokines by activated human T cells: Dependence on CD28 signaling and preferential inhibition of IL-10 production

Cytokine production upon T cell activation results from the integration of multiple signaling pathways from TCR/CD3 and from costimulatory molecules s uch as CD28. Among these pathways, the possible role of p38 mitogen activat ed protein kinase (MAPK) is the least understood. Here, we used a highly sp ecific p38 MAPK inhibitor, the SB203580 compound, to examine the role of th is enzyme in the induction of various cytokines in human T cells stimulated with anti-CD3 and anti-CD28 mAb together or in combination with PMA. Cytok ine induction was monitored by ELISA and at the mRNA level. While SB203580 had little effect on IL-2 production and proliferation, it significantly re duced the production of several other cytokines, The secretion of IL-4, IL- 5, IL-13, and TNF-alpha was inhibited by 20-50% with modes of T cell activa tion involving the CD28 pathway, whereas their mRNA expression was little a ffected. In contrast, IFN-gamma induction via CD28/PMA or CD3/CD28, but not CD3/PMA, was markedly diminished both at the protein and at the mRNA level s, Most interestingly, SB203580 also sup pressed IL-10 secretion and mRNA i nduction via CD28-dependent activation by 75-85% (IC50 similar to 0.2 mu M) . Subset analysis suggested that this inhibition did not reflect a differen tial effect on T cell subsets. Therefore, p38 MAPK activity appears to cont ribute to cytokine production, mostly via CD28-dependent signaling, Moreove r, IL-10 seems to rely more on this activity than other cytokines for its i nduction in T cells. (C) 1999 Academic Press.