CERAMIDE INDUCES INTERLEUKIN-6 GENE-EXPRESSION IN HUMAN FIBROBLASTS

We previously reported that ceramide, the immediate product of sphingo myelin hydrolysis, increases in response to interleukin (IL)-1 beta an d plays a sole in modulating IL-1 beta-mediated prostaglandin E(2) pro duction and cyclooxygenase gene expression in human fibroblasts (Ballo u, L. R., C. P. Chao, M. A. Holness, S. C. Backer, and R. Raghow. 1992 . J. Biol. Chem. 267:20044-20050), Here we describe the effects of cer amide in another IL-1 beta-mediated process in these cells, the induct ion of IL-6 production. We found that submicromolar concentrations of C-2-ceramide induced IL-6 gene expression and protein production as ef fectively as II-1 beta. Both D-erythro-C-2-ceramide (a cell-permeable analogue of natural ceramide) and D-threo-C-2-ceramide were potent ind ucers of IL-6 production, while neither L isomer of ceramide was effec tive. Compared with IL-1 beta-induced IL-6 production, cells treated w ith ceramide or exogenous sphingomyelinase induced 82 and 50% of maxim al IL-1 beta-induced IL-6 levels by 6 h, respectively; by 24 h all thr ee treatments induced similar levels of IL-6 production. Ceramide-indu ced IL-6 messenger RNA could be detected within 1 h of treatment and r eached maximal levels by 24 h. These findings suggest that ceramide ma y play a role in the regulation of IL-6 gene expression.