OPPOSING EFFECTS OF INTERFERON-GAMMA ON INOS AND INTERLEUKIN-10 EXPRESSION IN LIPOPOLYSACCHARIDE-STIMULATED AND MYCOBACTERIAL LIPOARABINOMANNAN-STIMULATED MACROPHAGES

Previous studies have demonstrated that, like bacterial lipopolysaccha ride (LPS), arabinofuranosyl-terminated lipoarabinomannan (AraLAM) fro m an attenuated strain of Mycobacterium induces potent early gene (c-f os, KC, JE and TNF-alpha) responses in murine macrophages, whereas ext ensively alpha-Manp capped LAM (ManLAM) from virulent M. tuberculosis do not. In this study we have extended analysis of the influence of my cobacterial LAM on macrophage function by demonstrating that AraLAM. ( but not ManLAM), like bacterial LPS, is a potent stimulator of inducib le nitric oxide synthase (iNOS) expression independent of the autocrin e activity of co-stimulated tumour necrosis factor-alpha (TNF-alpha) r elease. The inability of ManLAM to induce iNOS expression was not due to induction of the 'deactivating' cytokine interleukin-10 (IL-10). In deed, 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 a s a potent co-stimulus for iNOS, it completely inhibits the IL-10 resp onse. Hence, the presence of IFN-gamma early in infection, will have a n important immunomodulatory role in determining the macrophage respon se. These results have important implications for the pathogenesis of virulent and avirulent mycobacteria in vivo.