Endogenous TNF-α Modulates the Proliferation of Rat Mesangial Cells and Their Prostaglandin E2 Synthesis

Abstract

Mesangial cells (MC) are one cellular source of tumor necrosis factor alpha (TNF) within the kidney as shown by experimental stimulation with endotoxin. TNF was shown to increase MC synthesis of prostaglandins E 2 (PGE 2) which down regulate MC proliferation. The involvement of endogenous TNF as an autocrine factor to control MC proliferation is unknown. This role was evaluated in vitro by addition of anti-TNF immunoglobulins and soluble TNF receptor-I (sTNF-RI) on rat MC. Anti-TNF immunoglobulins and sTNF-RI induced a dose-dependent increase of cell proliferation when the cells were quiescent in 0.5% FCS ( P = 0.002). No effect was found when the cells were growing in 10% FCS ( P = 0.113). Incubation of MC with anti-TNF immunoglobulins resulted in a dose-dependent decrease of PGE 2 release. In order to investigate if the effect of TNF on MC proliferation was mediated by the decrease of PGE 2 release. PGE 2 was added to the culture medium at concentrations of 0.1 to 10 μ/ml in conjunction with anti-TNF immunoglobulins. PGE 2 did not modify the proliferation induced by anti-TNF immunoglobulins. We conclude that anti-TNF immunoglobulins and sTNF-RI promoted MC DNA synthesis and influenced their PGE 2 release by blocking the endogenous TNF. The mechanism of action on DNA synthesis was not mediated by PGE 2. This indicates that endogenous TNF has a substantial role in tile control of resting mesangial cells.