Abstract
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 3-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.
Highlights
Interleukin-10 (IL-10),1 originally identified as an inhibitor of cytokine synthesis by T-cells [1], was subsequently recognized to have a wide range of additional properties
The study shows that IL-10 activates PI 3-kinase and p70 S6 kinase in both primary monocytes and a murine mast cell line, D36
We investigated whether the proliferation of D36 cells was directly attributable to IL-10 or the result of the induction of an autocrine growth factor induced by the cytokine
Summary
Interleukin-10 (IL-10), originally identified as an inhibitor of cytokine synthesis by T-cells [1], was subsequently recognized to have a wide range of additional properties. It has potent antiinflammatory effects, suppressing the production of IL-1, tumor necrosis factor ␣ (TNF-␣), and ␥-interferon in polymorphonuclear cells [2] and monocytes [3] while increasing the release of soluble TNF receptor, a natural inhibitor of TNF-␣ function [4]. PI 3-kinase and p70 S6 kinase activation was not required for IL-10 suppression of lipopolysaccharide (LPS)-induced TNF-␣ or soluble TNF receptor production. These data indicate a selective role for PI 3-kinase and p70 S6 kinase in IL-10 function and suggest the existence of multiple pathways with different functional end points induced by IL-10
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