The role of TNF-alpha in T-cell-mediated inflammation depends on the Th1/Th2 cytokine balance.
The role of tumour necrosis factor-alpha (TNF-alpha) in tuberculosis is paradoxical because although there is much evidence for a protective role, there is also evidence that it plays a part in the tissue damage that characterizes human disease. We have shown previously that TNF-alpha frequently induces necrosis when injected into sites undergoing delayed-type hypersensitivity (DTH) responses to mycobacterial antigen. This is dependent on CD4+ T cells. However the presence of this sensitivity to TNF-alpha-induced necrosis depended on the immunization protocol. We have tested the hypothesis that sensitivity to TNF-alpha depends on the cytokine profile of the induced T-cell response. All subcutaneous doses of mycobacterial immunogen used (10(7) to 10(9) organisms) primed spleen cells so that they secreted interferon-gamma (IFN-gamma) and interleukin-2 (IL-2) when cultured in vitro with soluble antigen. However priming for production of IL-4 was dose dependent as in other systems, and was produced at all times from 7 to 30 days after immunization with 10(9) organisms. Time-course studies over 30 days showed that sensitivity to TNF-alpha was found in DTH sites of animals primed for IL-4 and IFN-gamma production, but not in animals primed only for the Th1 cytokines. We suggest therefore that the paradoxical role of TNF-alpha can be resolved. In 'pure' Th1 responses it may act as an additional macrophage-activating factor. In mixed Th1 + Th2 or Th0 responses it may cause tissue damage. This mixed pattern is characteristic of tuberculosis, and of the late stage of many chronic infections where elimination of the infecting organism is failing, and chronic tissue damage is seen.
Department of Pathology, Instituto Nacional de la Nutricion Salvador Zubiran, Mexico DF.
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Hernandez-Pando
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Rook
D000818:Animals; D000942:Antigens, Bacterial / Q000008:administration & dosage / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis*; D004306:Dose-Response Relationship, Immunologic; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007114:Immunization / Q000379:methods; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009161:Mycobacterium / Q000276:immunology*; D011994:Recombinant Proteins / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
D000942:Antigens, Bacterial; D016207:Cytokines; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D007371:Interferon-gamma