Suppression of IFNγ plus mycobacterial lipoarabinomannan-induced NO by IL-4 is due to decreased IRF-1 expression

In mice, and possibly in humans, nitric oxide (NO) is an important host-defense molecule against Mycobacterium tuberculosis. Inducible nitric oxide synthase (iNOS) and NO are upregulated in murine macrophages stimulated with interferon-gamma (IFN gamma) and mannose-capped lipoarabinomannan (ManLAM), a major lipoglycan in the cell wall of M. tuberculosis. Interleukin-4 (IL-4) can inhibit NO expression and may impair host immune response to M. tuberculosis. Therefore, we sought to determine the mechanism by which IL-4 inhibits IFN gamma + ManLAM-induced NO production. Since L-arginine is the substrate for both iNOS and arginase, and IL-4 increases arginase activity by inducing its production, a plausible mechanism of IL-4 inhibition of NO expression is via depletion of L-arginine through increased arginase activity. Herein, we show that IL-4 inhibited iNOS gene expression at the transcriptional level, suggesting an inhibitory mechanism that is independent of the competition for L-arginine between iNOS and arginase. Furthermore, pharmacologic inhibition of IL-4-induced arginase activity did not abrogate IL-4 inhibition of IFN gamma + ManLAM-induced NO expression. Instead, inhibition by IL-4 was mediated principally by the ability of IL-4 to inhibit the production of IFN gamma-induced interferon-gamma response factor-1 (IRF-1) protein, a critically important transcriptional element that enhances expression of IFN gamma-inducible genes such as iNOS. Published by Elsevier Ltd.