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 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.
Crawley
J B
JB
Kennedy Institute of Rheumatology, Sunley Division, 1 Lurgan Ave., Hammersmith, London W6 8LW, United Kingdom.
Williams
L M
LM
Mander
T
T
Brennan
F M
FM
Foxwell
B M
BM
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007375:Interleukin-1 / Q000096:biosynthesis; D016753:Interleukin-10 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008407:Mast Cells; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011090:Polyenes / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases; D015398:Signal Transduction; D020123:Sirolimus; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000077191:Wortmannin
D000730:Androstadienes; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002867:Chromones; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D007375:Interleukin-1; D016753:Interleukin-10; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011090:Polyenes; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; D020123:Sirolimus; D014409:Tumor Necrosis Factor-alpha; D000077191:Wortmannin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one