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

J Neurochem. 2000 Aug;75(2):576-82. doi: 10.1046/j.1471-4159.2000.0750576.x.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Androstadienes / pharmacology
  • Animals
  • Astrocytes / drug effects
  • Astrocytes / immunology
  • Astrocytes / metabolism*
  • Brain / cytology
  • Brain / metabolism
  • Cells, Cultured
  • Ceramides / metabolism*
  • Chromones / pharmacology
  • Diacylglycerol Kinase / metabolism
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Inflammation
  • Interleukin-1 / antagonists & inhibitors
  • Interleukin-1 / pharmacology*
  • Interleukin-10 / pharmacology*
  • Interleukin-13 / pharmacology*
  • Kinetics
  • Morpholines / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Rats
  • Sphingomyelins / metabolism
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Wortmannin


  • Androstadienes
  • Ceramides
  • Chromones
  • Enzyme Inhibitors
  • Interleukin-1
  • Interleukin-13
  • Morpholines
  • Sphingomyelins
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Phosphatidylinositol 3-Kinases
  • Diacylglycerol Kinase
  • Wortmannin