title: Interleukin-1 and endothelin stimulate distinct species of diglycerides that differentially regulate protein kinase C in mesangial cells.
abstract: Diglycerides are phospholipid-derived second messengers that serve as cofactors for protein kinase C activation. We have previously shown that, in rat glomerular mesangial cells, the cytokine, interleukin-1 alpha, and the vasoactive peptide, endothelin, generate diglycerides from unique phospholipid precursors. However, neither the molecular species of these diglycerides nor their biological actions were determined. It is now hypothesized that interleukin-1- and endothelin-treated mesangial cells form distinct molecular species of diglycerides which may serve different roles as intracellular signaling molecules. Diglyceride molecular species were resolved and quantified by TLC and high performance liquid chromatography as diglyceride-[14C]acetate derivatives. Endothelin stimulates predominantly ester-linked species (diacylglycerols) in contrast to interleukin-1 which stimulates only ether-linked species (alkyl, acyl- and alkenyl,acylglycerols). In support of these data, interleukin-1-treated mesangial cells hydrolyze ethanolamine plasmalogens, vinyl ether-linked phospholipids. It has been reported that ether-linked, in contrast to ester-linked, diglyceride species do not activate protein kinase C activity. Thus, we next assessed membrane protein kinase C activity in endothelin- or interleukin-1-treated mesangial cells. Even though interleukin-1 has no effect upon basal protein kinase C activity, this cytokine, through the formation of ether-linked diglyceride second messengers, inhibits endothelin, platelet-activating factor, or arginine vasopressin-stimulated protein kinase C activity. We further demonstrate that ester-linked diacylglycerols but not alkyl,acyl- or alkenyl,acylglycerols substitute for phorbol esters in a cell-free protein kinase C assay. In addition, alkenyl,acylglycerols inhibit diacylglycerol-stimulated immunoprecipitated protein kinase C alpha activity in vitro and total protein kinase C activity in permeabilized mesangial cells ex vivo. Taken together, these data suggest that interleukin-1-induced formation of ether-linked diglycerides may physiologically serve to down-regulate receptor-mediated protein kinase C activity and that individual molecular species of diglycerides may serve different roles as intracellular signaling molecules.
authors.affiliation: Department of Medicine and Physiology/Biophysics, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: A
authors.initials: A
authors.lastname: Musial
authors.forename: A
authors.initials: A
authors.lastname: Mandal
authors.forename: E
authors.initials: E
authors.lastname: Coroneos
authors.forename: M
authors.initials: M
authors.lastname: Kester
mesh_terms: D000085:Acetates / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000201:enzymology; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D004075:Diglycerides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D016232:Endothelins / Q000494:pharmacology*; D005920:Glomerular Mesangium / Q000201:enzymology*; D007375:Interleukin-1 / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D010743:Phospholipids / Q000378:metabolism; D010955:Plasmalogens / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D000085:Acetates; D004075:Diglycerides; D016232:Endothelins; D007375:Interleukin-1; D010743:Phospholipids; D010955:Plasmalogens; D011493:Protein Kinase C