Suppression of IFNgamma+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 (IFNgamma) 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 IFNgamma+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 IFNgamma+ManLAM-induced NO expression. Instead, inhibition by IL-4 was mediated principally by the ability of IL-4 to inhibit the production of IFNgamma-induced interferon-gamma response factor-1 (IRF-1) protein, a critically important transcriptional element that enhances expression of IFNgamma-inducible genes such as iNOS.
Morris
Kristin R
KR
Department of Medicine, University of Colorado Health Sciences Center, Denver, CO, USA.
Lutz
Ryan D
RD
Bai
Xiyuan
X
McGibney
Mischa T
MT
Cook
Danielle
D
Ordway
Diane
D
Chan
Edward D
ED
D000818:Animals; D001119:Arginase / Q000378:metabolism; D001120:Arginine / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology*; D020382:Interleukin-18 / Q000378:metabolism; D015847:Interleukin-4 / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000378:metabolism / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000276:immunology; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000235:genetics; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism
D050856:Interferon Regulatory Factor-1; D020382:Interleukin-18; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; C050016:lipoarabinomannan; D015847:Interleukin-4; D009569:Nitric Oxide; D007371:Interferon-gamma; D001120:Arginine; D052247:Nitric Oxide Synthase Type II; D001119:Arginase