NITRIC-OXIDE SYNTHESIS BY RAT PLEURAL MESOTHELIAL CELLS - INDUCTION BY CYTOKINES AND LIPOPOLYSACCHARIDE

The close proximity of pleural mesothelial cells (PMC) and mononuclear cells during pleural inflammation suggests that leukocyte-derived pro ducts (e.g., cytokines) may play an important role in modulating PMC f unction. The purpose of this study was to determine whether certain cy tokines and bacterial products induce PMC to produce nitric oxide (NO) . Confluent monolayers of rat PMC were exposed to tumor necrosis facto r (TNF), interleukin-1beta (IL-1), gamma-interferon (IFN), or lipopoly saccharide (LPS) individually and in various double and triple combina tions for 6-72 h. Concentrations of nitrite and nitrate were quantifie d and used as indirect indices of NO production. Nitrite/nitrate accum ulation was maximal at 72 h, with most of the increase occurring from 48 to 72 h. Maximal nitrite/nitrate production was observed with tripl e combinations with the combination of LPS, IL-1, and TNF giving the h ighest concentration (137.4 +/- 2.8 muM). Nitrite/nitrate production w as significantly inhibited by N(G)-nitro-L-arginine methyl ester, sugg esting that nitrite and nitrate were derived from the L-arginine-depen dent formation of NO. These data indicate that PMC can be induced to p roduce large amounts of NO in response to specific combinations of pro inflammatory cytokines and LPS.