IL-1beta induces VEGF, independently of PGE2 induction, mainly through the PI3-K/mTOR pathway in renal mesangial cells.
Vascular endothelial growth factor (VEGF) could play a relevant role in angiogenesis associated with chronic allograft nephropathy. Interleukin-1beta (IL-1beta) has a key role in inflammatory response. It induces prostaglandin (PG) E2, which is involved in VEGF release by some normal and tumor cells. In the present work, we studied the effect of IL-1beta on VEGF release by rat mesangial cells, the transduction signal, and whether or not PGE2 is involved in this effect. IL-1beta induced a time-dependent formation of VEGF (analyzed by enzyme-linked immunosorbent assay) and PGE2 (analyzed by enzyme immunoassay). The latter correlated with microsomal-PGE-synthase (mPGES)-1 expression rather than with cyclooxygenase (COX)-2 in terms of protein, determined by Western blotting. No effect of IL-1beta on COX-1, cytosolic PGES, or mPGES-2 expression was observed. Indomethacin exerted a nonsignificant effect on IL-1beta-induced VEGF, and exogenously added PGE2 exhibited a nonsignificant stimulatory effect on VEGF formation. SB 203580, a p38 mitogen-activated protein kinase inhibitor, weakly inhibited the induction of VEGF by IL-1beta in a concentration-dependent manner, whereas LY 294002, a phosphoinoside 3-kinase (PI3-K) inhibitor, and rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, strongly inhibited both IL-1beta- and tumor necrosis factor-alpha-induced VEGF formation in a concentration-dependent manner. Rapamycin also decreased glomerular VEGF levels in the anti-Thy1.1 model of experimental glomerulonephritis. In conclusion, the PI3-K-mTOR pathway seems to be essential in cytokine-induced release of VEGF in mesangial cells.
Solà-Villà
D
D
Inflammation Mediators Laboratory, Institute of Research of Hospital Santa Creu i Sant Pau, Barcelona, Spain.
Camacho
M
M
Solà
R
R
Soler
M
M
Diaz
J-M
JM
Vila
L
L
D000818:Animals; D002478:Cells, Cultured; D015232:Dinoprostone / Q000378:metabolism*; D053583:Interleukin-1beta / Q000502:physiology*; D050527:Mesangial Cells / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D015232:Dinoprostone; D053583:Interleukin-1beta; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D058570:TOR Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A; C546845:mTOR protein, rat