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

Abstract

Previous studies have shown that mast cell granules (MCG) inhibit numerous macrophage functions including tumour cytotoxicity, superoxide and nitric oxide (NO) production, and FCγ2a receptor-mediated phagocytosis. In this study, the effect of MCG on macrophage TNFα and nitric oxide synthase (iNOS) mRNA expression, and the production and fate of TNFα were examined. Upon activation with LPS+IFNγ, macrophages expressed both TNFα and iNOS mRNA and produced both TNFα and NO. Co-incubation of LPS+IFNγ-activated macrophages with MCG resulted in dose-dependent inhibition of iNOS mRNA expression. TNFα production in the activated macrophages was decreased by MCG, which was associated with a reduction in TNFα mRNA expression. MCG were also capable of degrading both macrophage-generated and recombinant TNFα. The direct effect of MCG on TNFα was partially reversed by a mixture of protease inhibitors. These results demonstrate that MCG decrease the production of NO and TNFα by inhibiting macrophage iNOS and TNFα gene expression. Furthermore, MCG post-transcriptionally alter TNFα levels via proteolytic degradation.