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 regula te 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) i n 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-l receptor-generated ether-linked diglycerides inhibit immunoprecipitated protein kinase C delta and epsilon but not zeta activity. Neither interleukin-1 not endothelin affect de novo pr otein expression of these protein kinase C isotypes. As down-regulatio n of calcium-insensitive protein kinase C isotypes has been linked to antimitogenic activity, we investigated growth arrest as a functional correlate for IL-l-generated ether-linked diglycerides. Cell-permeable ether-linked diglycerides mimic the effects of interleukin-1 to, indu ce a growth-arrested state in both G-protein-linked receptor- and tyro sine kinase receptor-stimulated mesangial cells. This signaling mechan ism 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.