Interleukin-1 production by mouse macrophages is regulated in a feedback fashion by nitric oxide

The pleiotropic cytokine interleukin-1 (IL-1) is an inducer of the inducibl e nitric oxide synthase (iNOS). It was surprising to find that treatment of normal mice with an iNOS inhibitor resulted in detectable IL-1 beta mRNA i n colon and spleen, suggesting feedback regulation. When mouse peritoneal e xudate cells (PEC) or RAW 264.7 cells were stimulated with lipopolysacchari de (LPS), concomitant inhibition of iNOS resulted in an increase of IL-1 be ta and IL-1 alpha protein secretion. Conversely, after addition of the NO-g enerating compound NOC-18, IL-1 beta and IL-1 alpha concentrations in super natants were dose-dependently reduced. Costimulation with interferon-gamma (IFN-gamma) reversed the NOC-18-mediated suppression of IL-1 alpha. protein concentration into an almost fivefold increase in RAW 264.7 cells. This ef fect was specific for IL-1 alpha and was also seen in PEG. The mRNA express ion for IL-1 beta and IL-1 alpha. in RAW 264.7 cells correlated with the pr otein. levels, suggesting transcriptional regulation by NO. Dysregulated IL -1/NO cross-regulation may play a role in inflammatory diseases.