Interleukin-1 beta induces chronic activation and de novo synthesis of neutral ceramidase in renal mesangial cells

R. Franzen et al., Interleukin-1 beta induces chronic activation and de novo synthesis of neutral ceramidase in renal mesangial cells, J BIOL CHEM, 276(38), 2001, pp. 35382-35389
Citations number
Categorie Soggetti
Biochemistry & Biophysics
Journal title
ISSN journal
0021-9258 → ACNP
Year of publication
35382 - 35389
SICI code
The lipid signaling molecule ceramide is formed by the action of acid and n eutral sphingomyelinases and degraded by acid and neutral ceramidases. Shor t-term stimulation of mesangial cells with the pro-inflammatory cytokine in terleukin-1 beta (IL-1 beta) leads to a rapid and transient increase in neu tral sphingomyelinase activity (Kaszkin, M., Huwiler, A., Scholz, K., van d en Bosch, H., and Pfeilschifter, J. (1998) FEBS Lett. 440,163-166). In this study, we report on a second delayed peak of activation occurring after ho urs of IL-1 beta treatment. This second phase of activation was first detec table after 2 h of treatment and steadily increased over the next 2 h, reac hing maximal values after 4 h. In parallel, a pronounced increase in neutra l ceramidase activity was observed, accounting for a constant or even decre ased level of ceramide after long-term IL-1 beta treatment, despite continu ous sphingomyelinase activation. The increase in neutral ceramidase activit y was due to expressional up-regulation, as detected by an increase in mRNA levels and enhanced de novo protein synthesis. The increase in neutral cer amidase protein levels and activity could be blocked dose-dependently by th e p38 MAPK inhibitor SB 202190, whereas the classical MAPK pathway inhibito r U0126 and the protein kinase C inhibitor Ro 318220 were ineffective. More over, cotreatment of cells for 24 h with IL-1 beta and SB 202190 led to an increase in ceramide formation. Interestingly, IL-1 beta -stimulated neutra l ceramidase activation was not reduced in mesangial cells isolated from mi ce deficient in MAPK-activated protein kinase-2, which is a downstream subs trate of p38 MAPK, thus suggesting that the p38 MAPK-mediated induction of neutral ceramidase occurs independently of the MAPK-activated protein kinas e-2 pathway. In summary, our results suggest a biphasic regulation of sphin gomyelin hydrolysis in cytokine-treated mesangial cells with delayed de nov o synthesis of neutral ceramidase counteracting sphingomyelinase activity a nd apoptosis. Neutral ceramidase may thus represent a novel cytoprotective enzyme for mesangial cells exposed to inflammatory stress conditions.