Glucocorticoids inhibit lipopolysaccharide-induced up-regulation of arginase in rat alveolar macrophages

1 As arginase by limiting nitric oxide (NO) synthesis may play a role in ai rway hyperresponsiveness and glucocorticoids are known to induce the expres sion of arginase I in hepatic cells, glucocorticoid effects on arginase in alveolar macrophages (AM Phi) were studied. 2 Rat AM Phi were cultured in absence or presence of test substances. There after, nitrite accumulation, arginase activity, and the expression pattern of inducible NO synthase, arginase I and II mRNA (RT-PCR) and proteins (imm unoblotting) were determined. 3 Lipopolyssacharides (LPS, 20 h) caused an about 2 fold increase in argina se activity, whereas interferon-gamma (IFN-gamma), like LPS a strong induce r of NO synthesis, had no effect. 4 Dexamethasone decreased arginase activity by about 25% and prevented the LPS-induced increase. Mifepristone (RU-486) as partial glucocorticoid recep tor agonist inhibited LPS-induced increase by 45% and antagonized the inhib itory effect of dexamethasone. 5 Two different inhibitors of the NF-kappaB-pathway also prevented LPS-indu ced increase in arginase activity. 6 Rat AM Phi expressed mRNA and protein of arginase I and II, but arginase I expression was stronger. Arginase I mRNA. and protein was not affected by IFN-gamma, but increased by LPS and this effect was prevented by dexametha sone. Both, LPS and IFN-gamma enhanced the levels of arginase II mRNA and p rotein, effects also inhibited by dexamethasone. As IFN-gamma did not affec t total arginase activity, arginase II may represent only a minor fraction of total arginase activity. 7 In rat AM Phi glucocorticoids inhibit LPS-induced up-regulation of argina se activity, an effect which may contribute to the beneficial effects of gl ucocorticoids in the treatment of inflammatory airway diseases.