Interleukin-1-induced ether-linked diglycerides inhibit calcium-insensitive protein kinase C isotypes. Implications for growth senescence.
It is hypothesized that inflammatory cytokines and vasoactive peptides stimulate distinct species of diglycerides that differentially regulate protein kinase C isotypes. In published data, we demonstrated that interleukin-1, in contrast to endothelin, selectively generates ether-linked diglyceride species (alkyl, acyl- and alkenyl, acylglycerols) in rat mesangial cells, a smooth muscle-like pericyte in the glomerulus. We now demonstrate both in intact cell and in cell-free preparations that these interleukin-1 receptor-generated ether-linked diglycerides inhibit immunoprecipitated protein kinase C delta and epsilon but not zeta activity. Neither interleukin-1 nor endothelin affect de novo protein expression of these protein kinase C isotypes. As down-regulation of calcium-insensitive protein kinase C isotypes has been linked to antimitogenic activity, we investigated growth arrest as a functional correlate for IL-1-generated ether-linked diglycerides. Cell-permeable ether-linked diglycerides mimic the effects of interleukin-1 to induce a growth-arrested state in both G-protein-linked receptor- and tyrosine kinase receptor-stimulated mesangial cells. This signaling mechanism implicates cytokine receptor-induced ether-linked diglycerides as second messengers that inhibit the bioactivity of calcium-insensitive protein kinase C isotypes resulting in growth arrest.
Mandal
A
A
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106-4949, USA.
Wang
Y
Y
Ernsberger
P
P
Kester
M
M
D000375:Aging / Q000378:metabolism*; D000818:Animals; D004075:Diglycerides / Q000378:metabolism*; D019332:Endothelin-1 / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D007375:Interleukin-1 / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon; D051381:Rats; D017207:Rats, Sprague-Dawley; D000099221:Protein Kinase C zeta
D004075:Diglycerides; D019332:Endothelin-1; D007375:Interleukin-1; D007527:Isoenzymes; D010982:Platelet-Derived Growth Factor; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon; D000099221:Protein Kinase C zeta; C497260:Prkcd protein, rat; C497257:Prkce protein, rat