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Infect Immun, May 1998, p. 2122-2127, Vol. 66, No. 5
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

A Tumor Necrosis Factor Mimetic Peptide Activates a Murine Macrophage Cell Line To Inhibit Mycobacterial Growth in a Nitric Oxide-Dependent Fashion

W. J. Britton,1,2,* N. Meadows,1 D. A. Rathjen,3,4 D. R. Roach,1 and H. Briscoe1,2

Centenary Institute of Cancer Medicine and Cell Biology, Newtown, New South Wales, 2042,1 Department of Medicine, University of Sydney, New South Wales, 2006,2 Peptech Limited, North Ryde, New South Wales, 2113,3 and Department of Immunopathology, Women's and Children's Hospital, North Adelaide, South Australia,4 Australia

Received 16 October 1997/Returned for modification 10 December 1997/Accepted 2 February 1998

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.

* Corresponding author. Mailing address: Centenary Institute of Cancer Medicine and Cell Biology, Locked Bag No. 6, Newtown, New South Wales, 2042, Australia. Phone: 61-2-9515 5210. Fax: 61-2-9351 3968. E-mail: wbritton{at}medicine.usyd.edu.au.

Infect Immun, May 1998, p. 2122-2127, Vol. 66, No. 5
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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Copyright © 1998 by the American Society for Microbiology. All rights reserved.