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Endogenous TNF-alpha modulates the proliferation of rat mesangial cells and their prostaglandin E2 synthesis
N M Benador1, G E Grau, C Ruef
1Department of Pediatrics, Hôpital Cantonal, Geneva, Switzerland.
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 E2 (PGE2) 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 PGE2 release. In order to investigate if the effect of TNF on MC proliferation was mediated by the decrease of PGE2 release, PGE2 was added to the culture medium at concentrations of 0.1 to 10 micrograms/ml in conjunction with anti-TNF immunoglobulins. PGE2 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 PGE2 release by blocking the endogenous TNF. The mechanism of action on DNA synthesis was not mediated by PGE2. This indicates that endogenous TNF has a substantial role in the control of resting mesangial cells.
Insights
Endogenous tumor necrosis factor alpha (TNF) controls resting kidney mesangial cell (MC) proliferation. Blocking TNF with antibodies or receptors increased MC DNA synthesis, independent of prostaglandin E2 (PGE2) release.
Area of Science:
- Nephrology
- Immunology
- Cell Biology
Background:
- Mesangial cells (MC) produce tumor necrosis factor alpha (TNF).
- TNF stimulates prostaglandin E2 (PGE2) synthesis in MC, which inhibits MC proliferation.
- The role of endogenous TNF in controlling MC proliferation is not well understood.
Purpose of the Study:
- To investigate the role of endogenous TNF as an autocrine factor controlling MC proliferation.
- To determine if TNF's effect on MC proliferation is mediated by PGE2.
Main Methods:
- Rat MC were cultured in varying serum concentrations.
- Anti-TNF antibodies and soluble TNF receptor-I (sTNF-RI) were added to MC cultures.
- Cell proliferation and PGE2 release were measured.
- PGE2 was added to cultures to assess its role in TNF-mediated effects.
Main Results:
- Anti-TNF treatments significantly increased MC proliferation in quiescent cells (0.5% FCS), but not in growing cells (10% FCS).
- Anti-TNF treatments decreased PGE2 release in a dose-dependent manner.
- Exogenous PGE2 did not alter the proliferative effect of anti-TNF treatments on MC.
Conclusions:
- Endogenous TNF significantly controls the proliferation of resting mesangial cells.
- Blocking endogenous TNF enhances MC DNA synthesis.
- The mechanism by which TNF influences MC proliferation is not mediated by PGE2.