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A tumor necrosis factor mimetic peptide activates a murine macrophage cell line to inhibit mycobacterial growth in a nitric oxide-dependent fashion.

Abstract
The control of mycobacterial infections depends on the cytokine-mediated activation of mononuclear phagocytes to inhibit the growth of intracellular mycobacteria. Optimal activation requires the presence of T-cell-derived gamma interferon (IFN-gamma) and other signals, including tumor necrosis factor (TNF). Recently, an 11-mer peptide based on amino acids 70 to 80 of the human TNF sequence, TNF(70-80), was found to have TNF mimetic properties, which include the activation of human and mouse neutrophils to kill Plasmodia spp. Therefore, we investigated the capacity of TNF(70-80) to activate the murine macrophage cell line RAW264.7 infected with the vaccine strain Mycobacterium bovis bacillus Calmette-Guérin (BCG). When RAW264.7 cells were pretreated with human TNF or TNF(70-80) in the presence of IFN-gamma, there was a dose-dependent reduction in the replication of BCG as measured by the uptake of 3H-labeled uracil and a concomitant release of nitric oxide as measured by the nitrite in the culture supernatants. TNF- or TNF(70-80)-induced macrophage activation was dependent on IFN-gamma and was inhibited by neutralizing monoclonal antibody to human TNF and by anti-IFN-gamma antisera. Both nitrite release and BCG growth inhibition were abrogated by competitive inhibitors of L-arginine, which blocked the activation of inducible nitric oxide synthase. A soluble form of the Type 1 TNF receptor blocked the activation of BCG-infected macrophages by human TNF and TNF(70-80), demonstrating that the effect of TNF(70-80) is dependent on signaling through TNF receptor I. The mimetic effects of TNF(70-80) on macrophage activation in vitro suggest that treatment with TNF(70-80) may modulate mycobacterial infections in vivo.
AuthorsW J Britton, N Meadows, D A Rathjen, D R Roach, H Briscoe
JournalInfection and immunity (Infect Immun) Vol. 66 Issue 5 Pg. 2122-7 (May 1998) ISSN: 0019-9567 [Print] United States
PMID9573098 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Peptide Fragments
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha
  • Nitric Oxide
  • Interferon-gamma
Topics
  • Animals
  • Cell Line
  • Humans
  • Interferon-gamma (pharmacology)
  • Macrophage Activation (drug effects)
  • Macrophages (drug effects)
  • Mice
  • Mycobacterium bovis (drug effects, growth & development)
  • Nitric Oxide (physiology)
  • Peptide Fragments (pharmacology)
  • Receptors, Tumor Necrosis Factor (physiology)
  • Tumor Necrosis Factor-alpha (pharmacology)

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