Interleukin-10 stimulation of phosphatidylinositol 3-kinase and p70 S6 kinase is required for the proliferative but not the antiinflammatory effects of the cytokine

Interleukin-10 (IL-10) is a powerful suppressor of the proinflammatory monokine production by lipopolysaccharide-stimulated monocytes as well as a T- and B-cell growth cofactor, The signal transduction cascades initiated by IL-10 ligation to its cognate receptor remain to be elucidated, Here, we demonstrate that in both primary monocytes and the D36 cell line, IL-10 rapidly and transiently stimulated phosphatidylinositol 5-kinase activity associated with the p85 subunit of the enzyme, IL-10 also activated p70 S6 kinase in both cell types, The activation of both of these kinases was sensitive to wortmannin, an inhibitor of phosphatidylinositol 3-kinase, The activation of p70 S6 kinase was also inhibited by the immunosuppressive drug rapamycin. Both rapamycin and wortmannin inhibited the IL-10-induced proliferation of D36 cells but in contrast had no effect on the antiinflammatory effects of the cytokine on lipopolysaccharide-stimulated monocytes, Similar results on D36 proliferation and lipopolysaccharide stimulated monocyte inhibition by IL-10 were obtained with another phosphatidylinositol 3-kinase inhibitor, LY294002, This suggests that the activation of phosphatidylinositol 3-kinase and p70 S6 kinase is involved in the proliferative functions of IL-10 and that other as yet uncharacterized pathways affect the suppressive effects on monocytes, indicating that multiple and distinct signaling pathways mediate the various pleiotropic activities of IL-10. Furthermore, these findings suggest that it may be possible in the future to modulate the antiinflammatory effects of IL-10 for therapeutic benefit without disrupting other functions of the cytokine.