Opposing effects of interferon-gamma on iNOS and interleukin-10 expression in lipopolysaccharide- and mycobacterial lipoarabinomannan-stimulated macrophages.
Previous studies have demonstrated that, like bacterial lipopolysaccharide (LPS), arabinofuranosyl-terminated lipoarabinomannan (AraLAM) from an attenuated strain of Mycobacterium induces potent early gene (c-fos, KC, JE and TNF-alpha) responses in murine macrophages, whereas extensively alpha-Manp capped LAM (ManLAM) from virulent M. tuberculosis do not. In this study we have extended analysis of the influence of mycobacterial LAM on macrophage function by demonstrating that AraLAM (but not ManLAM), like bacterial LPS, is a potent stimulator of inducible nitric oxide synthase (iNOS) expression independent of the autocrine activity of co-stimulated tumour necrosis factor-alpha (TNF-alpha) release. The inability of ManLAM to induce iNOS expression was not due to induction of the 'deactivating' cytokine interleukin-10 (IL-10). Indeed, like LPS, AraLAM was also a potent inducer of IL-10 expression. However, analysis of AraLAM- or LPS-induced responses in the presence of interferon-gamma (IFN-gamma) showed that, whereas IFN-gamma acts as a potent co-stimulus for iNOS, it completely inhibits the IL-10 response. Hence, the presence of IFN-gamma early in infection will have an important immunomodulatory role in determining the macrophage response. These results have important implications for the pathogenesis of virulent and avirulent mycobacteria in vivo.
Roach
T I
TI
University of Cambridge Clinical School, Department of Medicine, Addenbrooke's Hospital, Cambridge, UK.
Barton
C H
CH
Chatterjee
D
D
Liew
F Y
FY
Blackwell
J M
JM
D000594:Amino Acid Oxidoreductases / Q000096:biosynthesis*; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D001483:Base Sequence; D002478:Cells, Cultured; D007371:Interferon-gamma / Q000276:immunology*; D016753:Interleukin-10 / Q000096:biosynthesis*; D007700:Kinetics; D008070:Lipopolysaccharides / Q000276:immunology*; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000201:enzymology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009161:Mycobacterium / Q000276:immunology; D019001:Nitric Oxide Synthase; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000942:Antigens, Bacterial; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C050016:lipoarabinomannan; D016753:Interleukin-10; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases