![]() ![]() TNF-α is involved in the development of granulomas, since administration of neutralizing anti-TNF-α antibodies leads to granuloma regression and mycobacterial dissemination ( 3, 17, 19). An excess of TNF-α released into the blood can be detrimental for humans, as suggested by the observation that many symptoms of tuberculosis and chronic MAC infections related to TNF-α, such as fever and weight loss, are improved by thalidomide, a drug that selectively destabilizes TNF-α mRNA ( 15, 28). It is generally accepted that the final outcome of TNF-α expression in different infection models may depend on its site of action, its local concentration, and the duration of exposure. MAC can survive within macrophages (Mφ) and affect various physiological functions, including the production of tumor necrosis factor alpha (TNF-α), a cytokine of great importance for anti-MAC resistance in ex vivo and in vivo models ( 3, 4, 13). Organisms belonging to the Mycobacterium avium complex (MAC) are rarely pathogenic for healthy individuals but may become a major cause of disseminated bacterial infection in human immunodeficiency virus-infected patients ( 18). Overall, these observations suggest that upregulation of TNF-RII or sTNF-RII contributes to modulation of the TNF-α antibacterial activity in MAC infections. Administration of an antagonist anti-TNF-RII monoclonal antibody (MAb 6G1) to infected mice inhibited the bacterial growth in the spleen, suggesting that the TNF-RII and/or sTNF-RII was functionally involved in the mechanisms that control the infection. In a model in which overproduction of bioactive TNF-α was triggered in response to a second infection with MAC, an increased production of sTNF-RII by cultured splenocytes was also observed. The level of circulating soluble TNF-RII (sTNF-RII) was transiently increased after day 21. In the spleen, TNF-α and TNF-RII mRNA levels peaked on day 21 and then slowly decreased however, no increase in the level of TNF-RI mRNA was observed throughout these experiments. Infection developed in two phases: the first, up to day 21, was associated with rapid MAC multiplication in the spleen and a drop in the mycobacteremia, and the second was associated with control of the infection in both compartments. The bacterial growth and the production of tumor necrosis factor alpha (TNF-α) and TNF receptors (TNF-Rs) in the spleen and blood of BALB/c mice challenged with Mycobacterium avium complex (MAC) were monitored.
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