Enhancement of Antibacterial Activity of Clofazimine Against Mycobacterium avium-Mycobacterium Intracellulare Complex Infection Induced by IFN-gamma Is Mediated by TNF-alpha

J Antimicrob Chemother. 1997 Feb;39(2):189-97. doi: 10.1093/jac/39.2.189.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology*
  • Clofazimine / administration & dosage
  • Clofazimine / pharmacology*
  • Female
  • Interferon-gamma / pharmacology*
  • Liposomes
  • Macrophages / microbiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Mycobacterium avium Complex / drug effects*
  • Mycobacterium avium-intracellulare Infection / drug therapy
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / pharmacology*
  • omega-N-Methylarginine / pharmacology

Substances

  • Anti-Bacterial Agents
  • Liposomes
  • Tumor Necrosis Factor-alpha
  • omega-N-Methylarginine
  • Interferon-gamma
  • Clofazimine