Negative regulation of interleukin-1 beta-activated neutral sphingomyelinase by protein kinase C in rat mesangial cells

Endogenous ceramide is produced by the action of acidic or neutral sphingom yelinases (SMase) in response to stimuli such as proinflammatory cytokines or other inducers of stress. Interleukin-1 beta (IL-1 beta) is known to sti mulate ceramide formation in rat renal mesangial cells; however, the respec tive subtype of SMase and its regulation have not been investigated. We fou nd that IL-1 beta induced an increase in endogenous ceramide levels via the action of a neutral SMase but not an acidic SMase in rat mesangial cells. Cytokine-induced activation of neutral SMase was inhibited by stimulation o f protein kinase C (PKC) by the phorbol ester TPA which caused a reduction of ceramide back to control levels. This inhibitory effect of TPA was rever sed by the specific PKC-inhibitor Ro-318220, Long-term incubation (24 h) of mesangial cells with TPA, which downregulates PKC-alpha, -delta, and -epsi lon isoenzymes, resulted in a recovery of IL-1 beta-stimulated neutral SMas e activity as web as ceramide formation. These data implicate an important modulatory function of PKC in ceramide production in IL-1 beta-activated me sangial cells. (C) 1998 Federation of European Biochemical Societies.