DOUBLE-STRANDED RNA-INDUCED INDUCIBLE NITRIC-OXIDE SYNTHASE EXPRESSION AND INTERLEUKIN-1 RELEASE BY MURINE MACROPHAGES REQUIRES NF-KAPPA-B ACTIVATION

The effects of double-stranded RNA (synthetic polyi nosinic-polycytidy lic acid; poly(I-C)) on macrophage expression of inducible nitric-oxid e synthase (iNOS), production of nitric oxide, and release of interleu kin-1 (IL-1) were investigated. Individually, poly(I-C), interferon-ga mma (IFN-gamma), and lipopolysaccharide (LPS) stimulate late nitrite p roduction and iNOS expression by RAW 264.7 cells. In combination, the effects of poly(I-C) + IFN-gamma are additive, while poly(I-C) does no t further potentiate LPS-induced nitrite production. These re suits su ggest that poly(I-C) and LPS may stimulate iNOS expression by similar signaling pathways, which may be independent of pathways activated by IFN-gamma, LPS-induced iNOS expression is associated with the activati on of NF-kappa B. We show that inhibition of NF-kappa B by pyrrolidine dithiocarbamate prevents poly(I-C) + IFN-gamma-, poly(I-C) + LPS-, an d LPS-induced iNOS expression, nitrite production and I kappa B degrad ation by RAW 264.7 cells. The effects of poly(I-C) on iNOS expression appear to be cell-type specific. Poly(I-C), alone or in combination wi th IFN-gamma, does not stimulate, nor does poly(I-C) potentiate, IL-1- induced nitrite production by rat insulinoma RINm5F cells. In addition , we show that the combination of poly(I-C) + IFN-gamma stimulates iNO S expression, nitrite production I kappa B degradation, and the releas e of IL-1 by primary mouse macrophages, and these effects are prevente d by pyrrolidinedithiocarbamate. These findings indicate that double-s tranded RNA, in the presence of IFN-gamma, is a potent activator of ma crophages, stimulating iNOS expression, nitrite production, and IL-1 r elease by a mechanism which requires the activation of NF-kappa B.