ENHANCEMENT OF ANTIBACTERIAL ACTIVITY OF CLOFAZIMINE AGAINST MYCOBACTERIUM-AVIUM MYCOBACTERIUM-INTRACELLULARE COMPLEX INFECTION-INDUCED BY IFN-GAMMA IS MEDIATED BY TNF-ALPHA

The effects of interferon-gamma (IFN-gamma) and tumour necrosis factor -alpha (TNF-alpha) alone or in combination with free or liposomal clof azimine against Mycobacterium avium-Mycobacterium intracellulare compl ex (MAC) were investigated. Treatment of murine resident peritoneal ma crophages with 50 U/mL IFN-gamma (pre-infection) or 30 U/mL TNF-alpha (post-infection), caused significant reduction in intracellular MAC gr owth; this response was suppressed by anti-TNF-alpha antibodies or pen toxifylline. Activation of macrophages with IFN-gamma or TNF-alpha enh anced the intracellular activities of free and liposomal clofazimine a gainst MAC; the individual antimycobacterial activities of free and li posomal clofazimine, however, were comparable. In the beige mouse mode l, IFN-gamma was ineffective, while liposomal clofazimine significantl y decreased the infection in liver and spleen; the use of N-G-monometh yl-L-arginine, a nitric oxide inhibitor, enhanced the effect of IFN-ga mma against MAC infection. In addition, treatment of infected mice wit h either IFN-gamma or liposomal clofazimine significantly reduced the infection in peritoneal macrophages.