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Infection and Immunity, March 2005, p. 1367-1376, Vol. 73, No. 3
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.3.1367-1376.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Recombinant Guinea Pig Tumor Necrosis Factor Alpha Stimulates the Expression of Interleukin-12 and the Inhibition of Mycobacterium tuberculosis Growth in Macrophages

Hyosun Cho,1* Todd M. Lasco,1,{dagger} Shannon Sedberry Allen,1 Teizo Yoshimura,2 and David N. McMurray1

Department of Medical Microbiology and Immunology, The Texas A&M University System Health Science Center, College Station, Texas,1 Laboratory of Molecular Immunoregulation, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland2

Received 25 August 2004/ Returned for modification 4 October 2004/ Accepted 21 October 2004

Tumor necrosis factor alpha (TNF-{alpha}) plays an important role in the host immune response to infection with the intracellular pathogen Mycobacterium tuberculosis. It is essential for the formation of protective tuberculous granulomas and regulates the expression of other cytokines which contribute to a protective immune response. Interleukin-12 (IL-12) is known to promote a Th1 response, which is essential for antimycobacterial resistance. Recombinant guinea pig TNF-{alpha} (rgpTNF-{alpha}) protein (17 kDa) was purified, and its bioactivity was confirmed by its cytotoxicity for L929 fibroblasts. High titers of polyclonal anti-gpTNF-{alpha} antibody were obtained by immunization of rabbits. Resident alveolar and peritoneal macrophages were isolated from guinea pigs and infected with either the H37Ra or H37Rv strain of M. tuberculosis. The mRNA levels for TNF-{alpha} and IL-12 p40 were measured using real-time PCR. IL-12 p40 mRNA was up-regulated in a dose-dependent manner by rgpTNF-{alpha} alone. In infected macrophages, a lower dose of rgpTNF-{alpha} intensified the mRNA levels of TNF-{alpha} and IL-12 p40. However, higher doses of rgpTNF-{alpha} suppressed TNF-{alpha} and IL-12 p40 mRNA. The antimycobacterial activity of macrophages was assessed by metabolic labeling of M. tuberculosis with [3H]uracil. Resident alveolar and peritoneal macrophages treated with anti-gpTNF-{alpha} antibody to block endogenous TNF-{alpha} exhibited increased intracellular mycobacterial growth. These data suggest that the dose of TNF-{alpha} is crucial to the stimulation of optimal expression of protective cytokines and that TNF-{alpha} contributes to the control of mycobacterial replication to promote host resistance against M. tuberculosis.

* Corresponding author. Mailing address: Department of Medical Microbiology and Immunology, The Texas A&M University System Health Science Center, 407 Reynolds Medical Building, College Station, TX 77843-1114. Phone: (979) 845-3679. Fax: (979) 845-3479. E-mail: HScho{at}medicine.tamu.edu.

Editor: J. L. Flynn

{dagger} Present address: Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523-1682.

Infection and Immunity, March 2005, p. 1367-1376, Vol. 73, No. 3
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.3.1367-1376.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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