Enhancement of antibacterial activity of clofazimine against Mycobacterium avium-Mycobacterium intracellulare complex infection induced by IFN-γ is mediated by TNF-α

Abstract

The effects of interferon-γ (IFN-γ) and tumour necrosis factor-α (TNF-α) alone or in combination with free or liposomal clofazimine against Mycobacterium avium-Mycobacterium intracellulare complex (MAC) were investigated. Treatment of murine resident peritoneal macrophages with 50 U/mL IFN-γ (pre-infection) or 30 U/mL TNF-α (post-infection), caused significant reduction in intracellular MAC growth; this response was suppressed by anti-TNF-α antibodies or pentoxifylline. Activation of macrophages with IFN-γ or TNF-α enhanced the intracellular activities of free and liposomal clofazimine against MAC; the individual antimycobacterial activities of free and liposomal clofazimine, however, were comparable. In the beige mouse model, IFN-γ was ineffective, while liposomal clofazimine significantly decreased the infection in liver and spleen; the use of N(G)-monomethyl-L-arginine, a nitric oxide inhibitor, enhanced the effect of IFN-γ against MAC infection. In addition, treatment of infected mice with either IFN-γ or liposomal clofazimine significantly reduced the infection in peritoneal macrophages.