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.