Interleukin-1 generates transmembrane signals from phospholipids through novel pathways in cultured rat mesangial cells.
Although IL-1 stimulates cellular responses in both lymphoid and nonlymphoid cells, the second messengers by which IL-1 activates cells are unknown. Recombinant IL-1 alpha (rIL-1) is a comitogen for glomerular mesangial cells. Using this model we explored potential transmembrane signals by which IL-1 stimulates cellular responses. Certain mitogens hydrolyze inositol phospholipids by phospholipase C to generate 1,2-diacylglycerol, a cofactor for protein kinase C, and inositol (1,4,5)-trisphosphate, which mobilizes intracellular calcium. rIL-1 induced a peak increase in [3H]1,2-diacylglycerol formation at 1 min. Production of 1,2-diacylglycerol often parallels the generation of phosphatidic acid; however, rIL-1 stimulated [32P]phosphatidate formation only after 60 min. rIL-1 did not change the inositol phosphate or cytosolic free calcium concentrations, demonstrating that rIL-1 does not activate an inositol phospholipid-specific phospholipase C. [3H]Phosphorylethanolamine, but not [3H]phosphorylserine or [3H]phosphorylcholine, was maximally elevated at 1 min in mesangial cells incubated with rIL-1. Radioactivity incorporated into phosphatidylethanolamine but not phosphatidylcholine was also decreased in IL-1-stimulated mesangial cells compared with control at 1 min. These data suggest that rIL-1 activates a phospholipase C predominantly linked to phosphatidylethanolamine. In contrast to other mitogens, rIL-1 did not alter intracellular pH. Both 12-0-tetradecanoyl-phorbol-13-acetate, a homologue of 1,2-diacylglycerol, and phosphatidate but not phosphatidylcholine in the presence of 0.5% fetal bovine serum stimulated mesangial cell proliferation. rIL-1-induced cellular activation may be mediated, at least in part, by phospholipid-derived second messengers generated through novel pathways.
Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106.
M
M
Kester
M S
MS
Simonson
P
P
Mené
J R
JR
Sedor
D000818:Animals; D002478:Cells, Cultured; D004075:Diglycerides / Q000378:metabolism; D004789:Enzyme Activation; D005920:Glomerular Mesangium / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D007375:Interleukin-1 / Q000494:pharmacology*; D010743:Phospholipids / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
C011439:1,2-diacylglycerol; D004075:Diglycerides; D007375:Interleukin-1; D010743:Phospholipids; D011994:Recombinant Proteins; D013755:Tetradecanoylphorbol Acetate