Differential regulation of sphingomyelinase and ceramidase activities by growth factors and cytokines. Implications for cellular proliferation and differentiation.
Sphingosine is a product of sphingolipid metabolism that has been linked to a protein kinase C-independent mitogenic response. In previously published data, utilizing an in vitro model system for platelet-derived growth factor (PDGF)-induced vascular smooth muscle proliferation, we have demonstrated that sphingosine is increased at the expense of a concomitant decrease in ceramide formation, implicating an altered ceramidase activity. To explore mechanisms of growth factor-stimulated sphingosine formation, we have developed and investigated a cell-free model system assessing ceramidase activity. We now report that an alkaline, membrane-associated, ceramidase activity in the rat glomerular mesangial cell, a smooth muscle-like pericyte, is up-regulated by growth factors, apparently via a tyrosine kinase phosphorylation mechanism. PDGF also stimulated sphingomyelinase activity which generates sufficient substrate to drive the subsequent ceramidase reaction. Inflammatory cytokines, including interleukin-1, and tumor necrosis factor-alpha, stimulated sphingomyelinase but not ceramidase activity, a result consistent with the cellular accumulation of the ceramide, apoptidic, differentiating second messenger. Mitogenic vasoconstrictor peptides such as endothelin-1 stimulated neither sphingomyelinase nor ceramidase activities. An inhibitor of ceramidase activity, N-oleoylethanolamine, reduced PDGF- but not endothelin-1-stimulated proliferation. Thus, we conclude that, in mesangial cells, growth factors but not vasoconstrictor peptides or cytokines induce mitogenesis, in part, through ceramidase-mediated sphingosine formation.
Coroneos
E
E
Department of Medicine, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106, USA.
Martinez
M
M
McKenna
S
S
Kester
M
M
D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002474:Cell-Free System; D055572:Ceramidases; D016207:Cytokines / Q000494:pharmacology*; D063388:Endocannabinoids; D016232:Endothelins / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004983:Ethanolamines / Q000494:pharmacology; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006133:Growth Substances / Q000494:pharmacology*; D009829:Oleic Acids; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*; D013110:Sphingosine / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D016207:Cytokines; D063388:Endocannabinoids; D016232:Endothelins; D004791:Enzyme Inhibitors; D004983:Ethanolamines; D006133:Growth Substances; D009829:Oleic Acids; D010982:Platelet-Derived Growth Factor; D014662:Vasoconstrictor Agents; C033595:N-oleoylethanolamine; D011505:Protein-Tyrosine Kinases; D013108:Sphingomyelin Phosphodiesterase; D000581:Amidohydrolases; D055572:Ceramidases; D013110:Sphingosine