Effect of mast cell granules on the gene expression of nitric oxide synthase and tumour necrosis factor-alpha in macrophages

PREVIOUS studies have shown that mast cell granules (MCG) inhibit numerous macrophage functions including tumour cytotoxicity, superoxide and nitric o xide (NO) production, and FC gamma 2a receptor-mediated phagocytosis. In th is study, the effect of MCG on macrophage TNF alpha and nitric oxide syntha se (iNOS) mRNA expression, and the production and fate of TNF alpha were ex amined. Upon activation with LPS+IFN gamma, macrophages expressed both TNF alpha and iNOS mRNA and produced both TNF alpha and NO. Co-incubation of LP S+IFN gamma-activated macrophages with MCG resulted in dose-dependent inhib ition of iNOS mRNA expression. TNF alpha production in the activated macrop hages was decreased by MCG, which was associated with a reduction in TNF al pha mRNA expression MCG were also capable of degrading both macrophage-gene rated and recombinant TNF alpha. The direct effect of MCG on TNF alpha was partially reversed by a mixture of protease inhibitors. These results demon strate that MCG decrease the production of NO and TNF alpha by inhibiting m acrophage iNOS and TNF alpha gene expression. Furthermore, MCG post-transcr iptionally alter TNF alpha levels via proteolytic degradation.