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Interleukin-6 antagonizes tumor necrosis factor-mediated mycobacteriostatic and mycobactericidal activities in
L E Bermudez1, M Wu, M Petrofsky
1Kuzell Institute for Arthritis and Infectious Diseases, Medical Research Institute of San Francisco, Pacific Presbyterian Medical Center, California 94115.
Insights
Interleukin-6 (IL-6) release by Mycobacterium avium-infected macrophages impairs tumor necrosis factor (TNF) activity. This suggests IL-6 influences host immune response and disease outcome in AIDS patients with M. avium infection.
Area of Science:
- Immunology
- Microbiology
- Cell Biology
Background:
- Interleukin-6 (IL-6) is a key cytokine in inflammatory responses, produced by cells like macrophages.
- Mycobacterium avium complex (M. avium) frequently causes disseminated infections in patients with Acquired Immunodeficiency Syndrome (AIDS).
- M. avium are intracellular bacteria that primarily infect macrophages, crucial cells in the immune system.
Purpose of the Study:
- To investigate the effect of IL-6 on the interaction between M. avium and macrophages.
- To determine if IL-6 influences the ability of tumor necrosis factor (TNF) to control intracellular M. avium.
- To explore the mechanism by which IL-6 might affect TNF activity, specifically receptor expression.
Main Methods:
- Cultured macrophage monolayers infected with M. avium were treated with recombinant IL-6.
- The capacity of TNF to inhibit or kill intracellular M. avium was assessed.
- Binding of labeled TNF (125I-TNF) to macrophages pre-exposed to IL-6 was measured to evaluate TNF receptor expression.
- IL-6 production by M. avium-infected macrophages was quantified over time.
Main Results:
- Recombinant IL-6 significantly reduced TNF-mediated inhibition of intracellular M. avium growth (68% decrease).
- IL-6 exposure led to a substantial decrease in TNF receptor expression on macrophages (78% reduction), an effect observed within 4 hours and reversible.
- M. avium infection stimulated IL-6 release from macrophages, peaking at 48 hours post-infection.
- IL-6 did not affect the growth rate of M. avium within or outside macrophages.
Conclusions:
- IL-6 released by M. avium-infected macrophages downregulates TNF receptors.
- This downregulation impairs TNF's ability to activate macrophages against M. avium.
- IL-6 produced during M. avium infection may modulate the host immune response and impact disease progression in AIDS patients.
Abstract:
Interleukin-6 (IL-6) is a cytokine produced by a number of cells, including macrophages, and is directly involved in the inflammatory response. The production of IL-6 can be stimulated by monokines such as IL-1 and tumor necrosis factor (TNF). Mycobacterium avium complex organisms frequently cause disseminated disease in patients with AIDS. M. avium is an intracellular bacterium that that mainly infects macrophages. Treatment of M. avium-infected macrophage monolayers with recombinant IL-6 decreased the ability of TNF to activate cultured macrophages to inhibit growth of or kill intracellular M. avium (68% +/- 14% decrease in intracellular killing compared with that in monolayers not treated with IL-6). To further evaluate whether this effect was dependent on the down regulation of membrane receptors to TNF, we examined 125I-TNF binding to macrophages previously exposed to IL-6: the expression of TNF receptors was decreased by 78% +/- 9%. The effect of IL-6 on TNF receptors was observed after 4 h and was reversible. Infection of macrophages with different M. avium serovars was associated with release of IL-6, and IL-6 production peaked at 48 h after infection in concentrations ranging from 328 +/- 87 ng/10(5) cells to 907 +/- 224 ng/10(5) cells. IL-6 did not have any influence on the rate of growth of the tested strains of M. avium within or outside macrophages. These results suggest that release of IL-6 by M. avium-infected macrophages may influence the host's immune response and the outcome of the disease.
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