LIPOPROTEIN-LIPASE SYNERGIZES WITH INTERFERON-GAMMA TO INDUCE MACROPHAGE NITRIC-OXIDE SYNTHETASE MESSENGER-RNA EXPRESSION AND NITRIC-OXIDE PRODUCTION

Lipoprotein lipase (LPL) induces macrophage tumor necrosis factor-alpha (TNF-alpha) gene expression and protein secretion. Since TNF-alpha can increase interferon gamma (IFN-gamma)-dependent nitric oxide (NO) production, we studied whether LPL may synergize with IFN-gamma for the induction of macrophage NO production. Although ineffective by itself, LPL in combination with IFN-gamma increased L-arginine-dependent NO production in a dose-dependent manner. Preincubation of LPL with an anti-LPL neutralizing antibody totally suppressed this effect. Increased NO synthetase (NOS) mRNA expression was also observed after macrophage treatment with IFN-gamma and LPL. Protein synthesis was required for the induction of NOS mRNA, and a TNF-alpha-mediated effect of LPL on NOS gene expression and NO production was observed. The ability of LPL to augment IFN-gamma-dependent NOS mRNA expression was associated with an increase in the NOS gene transcriptional activity but not in the NOS mRNA stability. Finally, binding of nuclear proteins to the nuclear factor-kappa B- and TNF-alpha-responsive sequences of the macrophage NOS promotor was decreased by treatment of the cells by IFN-gamma alone or in combination with LPL. These data provide evidence for a link between LPL and arginine metabolism in macrophages and further stress the role of LPL in the regulation of macrophage activation.