Mechanism of suppression of nitric oxide synthase expression by interleukin-4 in primary mouse macrophages

Abstract

Nitric oxide (NO) contributes to the anti-tumor, antimicrobial, and immunosuppressive activity of macrophages. An inducible form of NO synthase (iNOS) is responsible for high output generation of nitric oxide by macrophages after stimulation with cytokines and/or lipopolysaccharide (LPS). In the present study, we demonstrate that interleukin 4 (IL-4) suppressed production of NO by primary mouse peritoneal macrophages exposed to IFN-γ with or without LPS, even while synergizing with IFN-γ to increase the secretion of TNF-α. Suppression of NO production was paralleled by decreases in iNOS enzyme activity and iNOS antigen. IL-4 did not inhibit induction of iNOS mRNA 4–6 h after exposure to IFN-γ, but strongly reduced iNOS mRNA at later times of stimulation (24–72 h), without increasing its turnover. The conditions for maximal suppression of iNOS expression by IL-4 and the mechanisms of suppression differed from those determined in parallel for transforming growth-factor-β as described elsewhere. These results illustrate the diversity of phenotypes of macrophages deactivated by different cytokines, and demonstrate that IL-4 has the potential to reduce one component of the anti-tumor, antimicrobial, and immunosuppressive activities of macrophages. J. Leukoc. Biol. 55: 227–233; 1994.