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 clofazimine against Mycobacterium avium-Mycobacterium intracellulare complex (MAC) were investigated. Treatment of murine resident peritoneal macrophages with 50 U/mL IFN-gamma (pre-infection) or 30 U/mL TNF-alpha (post-infection), caused significant reduction in intracellular MAC growth; this response was suppressed by anti-TNF-alpha antibodies or pentoxifylline. Activation of macrophages with IFN-gamma or TNF-alpha 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-gamma 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-gamma against MAC infection. In addition, treatment of infected mice with either IFN-gamma or liposomal clofazimine significantly reduced the infection in peritoneal macrophages.
Gomez-Flores
R
R
Department of Bioimmunotherapy, The University of Texas M. D. Anderson Cancer Center, Houston, USA.
Tucker
S D
SD
Kansal
R
R
Tamez-Guerra
R
R
Mehta
R T
RT
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002991:Clofazimine / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D007371:Interferon-gamma / Q000494:pharmacology*; D008081:Liposomes; D008264:Macrophages / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D015269:Mycobacterium avium Complex / Q000187:drug effects*; D015270:Mycobacterium avium-intracellulare Infection / Q000188:drug therapy; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000494:pharmacology*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D008081:Liposomes; D014409:Tumor Necrosis Factor-alpha; D019323:omega-N-Methylarginine; D007371:Interferon-gamma; D002991:Clofazimine