Role of IFN-gamma on dissociation between nitric oxide and TNF/IL-6 production by murine peritoneal cells after restimulation with bacterial lipopolysaccharide

Murine peritoneal exudate cells (PEC) pre-exposed to bacterial lipopolysacc haride (LPS) show augmented nitric oxide (NO) production by LPS restimulati on, in contrast to LPS tolerance with reduced production of tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6), Significant amounts of i nterferon-gamma (IFN-gamma) were detected in the PEC cultures on LPS stimul ation, and anti-IFN-gamma antibody suppressed the LPS-induced NO, but not T NF-alpha and IL-6, production. Addition of anti-IFN-gamma antibody to the c ultures in the LPS pre-exposure step strongly suppressed the augmented NO p roduction on LPS restimulation. Anti-IL-12 antibody, which suppressed the L PS-induced IFN-gamma production, also suppressed the augmented NO productio n, as did anti-IFN-gamma antibody. Taken together, we propose the following mechanisms: (I) T and NK cells hr PEC produce IFN-gamma by the action of I L-12, which is derived from LPS-stimulated macrophages, and (2) the de novo -produced IFN-gamma activates macrophages to augment NO production on LPS r estimulation.