Interleukin-10 and interleukin-13 inhibit proinflammatory cytokine-induced ceramide production through the activation of phosphatidylinositol 3-kinase.
Ceramide produced by hydrolysis of plasma membrane sphingomyelin (SM) in different cells including brain cells in response to proinflammatory cytokines [tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta)] plays an important role in coordinating cellular responses to stress, growth suppression, and apoptosis. The present study underlines the importance of IL-10 and IL-13, cytokines with potent antiinflammatory properties, in inhibiting the proinflammatory cytokine (TNF-alpha and IL-1beta)-mediated degradation of SM to ceramide in rat primary astrocytes. Treatment of rat primary astrocytes with TNF-alpha or IL-1beta led to rapid degradation of SM to ceramide, whereas IL-10 and IL-13 by themselves were unable to induce the degradation of SM to ceramide. Interestingly, both IL-10 and IL-13 prevented proinflammatory cytokine-induced degradation of SM to ceramide. Both IL-10 and IL-13 caused rapid activation of phosphatidylinositol (PI) 3-kinase, and inhibition of that kinase activity by wortmannin and LY294002 potently blocked the inhibitory effect of IL-10 and IL-13 on proinflammatory cytokine-mediated induction of ceramide production. This study suggests that the inhibition of proinflammatory cytokine-mediated degradation of SM to ceramide by IL-10 and IL-13 is mediated through the activation of PI 3-kinase. As ceramide induces apoptosis and IL-10 and IL-13 inhibit the induction of ceramide production, we examined the effect of IL-10 and IL-13 on proinflammatory cytokine-mediated apoptosis. Inhibition of TNF-alpha-induced apoptosis by IL-10 and IL-13 suggests that the antiapoptotic nature of IL-10 and IL-13 is probably due to the inhibition of ceramide production.
Pahan
K
K
Department of Oral Biology, University of Nebraska Medical Center, Lincoln, Nebraska, USA.
Khan
M
M
Singh
I
I
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism*; D002867:Chromones / Q000494:pharmacology; D019852:Diacylglycerol Kinase / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007249:Inflammation; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D016753:Interleukin-10 / Q000494:pharmacology*; D018793:Interleukin-13 / Q000494:pharmacology*; D007700:Kinetics; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051381:Rats; D013109:Sphingomyelins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000077191:Wortmannin
D000730:Androstadienes; D002518:Ceramides; D002867:Chromones; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D018793:Interleukin-13; D009025:Morpholines; D013109:Sphingomyelins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D019852:Diacylglycerol Kinase; D000077191:Wortmannin