Laboratory Investigation

Kidney International (1989) 35, 1111–1118; doi:10.1038/ki.1989.98

Production of tumor necrosis factor by rat mesangial cells in response to bacterial lipopolysaccharide

Laurent Baud1, Jean-Paul Oudinet1, Marcelle Bens1, Lydie Noe1, Marie-Noëlle Peraldi1, Eric Rondeau1, Jacqueline Etienne1 and Raymond Ardaillou1

1Institut National de la Santé et de la Recherche Médicale, Unité 64, Hôpital Tenon, Paris, France

Correspondence: Dr L Baud, Hôpital Tenon, 4 rue de la Chine, 75020 Paris, France.

Received 9 June 1988; Revised 7 December 1988; Accepted 20 December 1988.

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Abstract

Production of tumor necrosis factor by rat mesangial cells in response to bacterial lipopolysaccharide. Tumor necrosis factor (TNF) is a cytokine which is produced by mononuclear phagocytes upon activation by bacterial lipopolysaccharide (LPS) and various other stimuli. In immune-mediated glomerulonephritis, infiltration of glomeruli by monocytes-macrophages is associated with production of TNF. The purpose of the present experiments was to determine whether mesangial cells could also contribute to glomerular TNF synthesis. TNF activity has been determined in the culture medium of rat mesangial cells using a L-929 fibroblast lytic assay. This activity was detectable only when the cells were exposed to LPS (0.1 to 10 microg/ml) and for periods longer than one hour. The cytotoxic factor was identified as TNF since: (1) the lytic activity was completely inhibited by an anti-mouse TNF polyclonal antibody and was associated with suppression of lipoprotein lipase activity in adipocytes; (2) its molecular weight (110,000 daltons) corresponded to that observed for murine TNF under non-denaturing conditions; and (3) mRNA encoding TNF was expressed by mesangial cells two hours after addition of LPS. To assess the mechanisms whereby TNF production was regulated, the role of prostaglandin E2 (PGE2) was determined. LPS caused a dose-dependent increase of PGE2 synthesis by mesangial cells. Treatment by indomethacin promoted a suppression of PGE2 production together with an increase of TNF synthesis, indicating that PGE2 acted in a negative feedback manner to regulate the production of TNF. Addition of PGE2 (0.1 to 300 nM) or 8-bromo cyclic AMP (0.1 to 100 microM) induced similar dose-dependent reductions of TNF synthesis. Thus the inhibitory effect of PGE2 probably required in part cyclic AMP accumulation. It is concluded that TNF is released by mesangial cells upon stimulation by LPS, and that its synthesis is regulated by both PGE2 and cyclic AMP. Production of TNF could participate in the mechanism of endotoxin-induced glomerular injury.

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