Ceramide induces interleukin 6 gene expression in human fibroblasts

We previously reported that ceramide, the immediate product of sphingomyelin hydrolysis, increases in response to interleukin (IL)-1β and plays a role in modulating IL-1β-mediated prostaglandin E₂ production and cyclooxygenase gene expression in human fibroblasts (Ballou, L. R., C. P. Chao, M. A. Holness, S.C. Barker, and R. Raghow. 1992. J, Biol. Chem. 267:20044-20050). Here we describe the effects of ceramide in another IL-1β- mediated process in these cells, the induction of IL-6 production. We found that submicromolar concentrations of C₂-ceramide induced IL-6 gene expression and protein production as effectively as IL-1β. Both D-erythro- C₂-ceramide (a cell-permeable analogue of natural ceramide) and D-threo- C₂-ceramide were potent inducers of IL-6 production, while neither L isomer of ceramide was effective. Compared with IL-1β-induced IL-6 production, cells treated with ceramide or exogenous sphingomyelinase induced 82 and 50% of maximal IL-1β-induced IL-6 levels by 6 h, respectively; by 24 h all three treatments induced similar levels of IL-6 production. Ceramide-induced IL-6 messenger RNA could be detected within 1 h of treatment and reached maximal levels by 24 h. These findings suggest that ceramide may play a role in the regulation of IL-6 gene expression.