REGULATION OF INDUCIBLE NITRIC-OXIDE SYNTHASE MESSENGER-RNA LEVELS BY LPS, INF-GAMMA, TGF-BETA, AND IL-10 IN MURINE MACROPHAGE CELL-LINES AND RAT PERITONEAL-MACROPHAGES

The molecular mechanisms of LPS, INF-gamma, TGF-beta, and IL-10 regulation of inducible nitric oxide synthase (iNOS) mRNA expression were evaluated. In murine macrophage cell lines, LPS-induced increases in iNOS mRNA were blocked by either cycloheximide or actinomycin D. Neither TGF-beta nor IL-10 alone had any effect on basal expression, and each only slightly reduced LPS induction of iNOS mRNA. However, IL-10 augmented INF-gamma induction of iNOS mRNA to very high levels, while TGF-beta inhibited INF-gamma induction. Human monocytes expressed no detectable iNOS mRNA with any stimuli, though Southern analysis on human genomic DNA revealed a specific human iNOS gene. In human macrophages, the iNOS gene may have become inoperative during evolution. (C) 1994 Academic Press, Inc.