SPHINGOLIPID METABOLITES DIFFERENTIALLY REGULATE EXTRACELLULAR SIGNAL-REGULATED KINASE AND STRESS-ACTIVATED PROTEIN-KINASE CASCADES

The mitogen-activated protein kinase (MAPK) signalling pathway serves to translocate information from activated plasmamembrane receptors to initiate nuclear transcriptional events. This cascade has recently bee n subdivided into two analogous pathways: the extracellular signal-reg ulated kinase (ERK) cascade, which preferentially signals mitogenesis, and the stress-activated protein kinase (SAPK) cascade, which is link ed to growth arrest and/or cellular inflammation. In concurrent experi ments utilizing rat glomerular mesangial cells (MCs), we demonstrate t hat growth factors or sphingosine activate ERK but not SAPK. In contra st, inflammatory cytokines or cell-permeable ceramide analogues activa te SAPK but not ERK. Ceramide, but not sphingosine, induces interleuki n-6 secretion, a marker of an inflamed phenotype. Moreover, ceramide c an suppress growth factor- or sphingosine-induced ERK activation as we ll as proliferation. These studies implicate sphingolipid metabolites as opposing regulators of cell proliferation and inflammation through activation of separate kinase cascades.