Interleukin-10 and interleukin-13 inhibit proinflammatory cytokine-inducedceramide production through the activation of phosphatidylinositol 3-kinase

Ceramide produced by hydrolysis of plasma membrane sphingomyelin (SM) in di fferent cells including brain cells in response to proinflammatory cytokine s [tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta)] plays an important role in coordinating cellular responses to stress, grow th suppression, and apoptosis. The present study underlines the importance of IL-10 and IL-13, cytokines with potent antiinflammatory properties, in i nhibiting the proinflammatory cytokine (TNF-alpha and IL-1 beta)-mediated d egradation of SM to ceramide in rat primary astrocytes. Treatment of rat pr imary astrocytes with TNF-alpha or IL-1 beta led to rapid degradation of SM to ceramide, whereas IL-10 and IL-13 by themselves were unable to induce t he degradation of SM to ceramide. interestingly, both IL-10 and IL-13 preve nted proinflammatory cytokine-induced degradation of SM to ceramide, Both I L-10 and IL-13 caused rapid activation of phosphatidylinositol (PI) 3-kinas e, and inhibition of that kinase activity by wortmannin and LY294002 potent ly blocked the inhibitory effect of IL-10 and IL-13 on proinflammatory cyto kine-mediated induction of ceramide production. This study suggests that th e inhibition of proinflammatory cytokine-mediated degradation of SM to cera mide 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 proinflam matory cytokine-mediated apoptosis, Inhibition of TNF-alpha-induced apoptos is by IL-10 and IL-13 suggests that the antiapoptotic nature of IL-10 and I L-13 is probably due to the inhibition of ceramide production.