Involvement of reactive oxygen intermediates in tumor necrosis factor alpha-dependent bacteriostasis of Mycobacterium avium.

ABSTRACT Increased production of tumor necrosis factor alpha (TNF-α) appears to play an important role in the progression of human immunodeficiency virus disease. One treatment strategy being explored is the use of TNF-α inhibitors. TNF-α also appears to be important in conferring resistance to infections, and the inhibition of this cytokine may exacerbate the emergence of opportunistic pathogens, such as Mycobacterium avium complex (MAC). The present study examines the possibility that inhibition of TNF-α will increase the progression of disease in mice infected with MAC. C57BL/6 beige (bg/bg) mice have been shown to be highly susceptible to infection with MAC and are routinely used for testing of antimycobacterial drugs. However, bg/bg mice are known to exhibit impaired phagocyte and natural killer cell function. Since these cell types are important sources of TNF-α, the susceptibility of the bg/bg strain to infection with MAC was compared with those of the heterozygous (bg/+) and wild-type (+/+) strains of C57BL/6 mice. The susceptibilities of the bg/bgand bg/+ strains of mice infected with MAC were found to be comparable. The +/+ strain was the least susceptible. Mycobacterial burden and serum TNF-α levels increased over time in all the strains of mice tested. The bg/+ strain of C57BL/6 mice was then chosen to measure the activity of TNF-α antagonists. Treatment with dexamethasone decreased serum TNF-α levels and increased mycobacterial burden. Treatment with anti-TNF-α antibody or pentoxifylline did not significantly alter serum TNF-α levels but increased mycobacterial burden. Treatment with thalidomide neither consistently altered mycobacterial burden in the spleens or livers of infected mice nor affected serum TNF-α levels.

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Upregulation of p75 Tumor Necrosis Factor Alpha Receptor in Mycobacterium avium-Infected Mice: Evidence for a Functional Role

Infection and Immunity ◽

10.1128/iai.67.11.5762-5767.1999 ◽

1999 ◽

Vol 67 (11) ◽

pp. 5762-5767 ◽

Cited By ~ 10

Author(s):

Angelo Corti ◽

Lanfranco Fattorini ◽

Ove Fredrik Thoresen ◽

Maria Luisa Ricci ◽

Anna Gallizia ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Mycobacterium Avium ◽

Bacterial Growth ◽

Tumor Necrosis ◽

Mrna Levels ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Factor Alpha ◽

Necrosis Factor

ABSTRACT 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. 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. 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. The level of circulating soluble TNF-RII (sTNF-RII) was transiently increased after day 21. 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. 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. Overall, these observations suggest that upregulation of TNF-RII or sTNF-RII contributes to modulation of the TNF-α antibacterial activity in MAC infections.

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