Innate inhibition of adaptive immunity: Mycobacterium tuberculosis-induced IL-6 inhibits macrophage responses to IFN-γ

V Nagabhushanam, A Solache, LM Ting… - The Journal of …, 2003 - journals.aai.org
V Nagabhushanam, A Solache, LM Ting, CJ Escaron, JY Zhang, JD Ernst
The Journal of Immunology, 2003journals.aai.org
In humans and in mice, control of the intracellular pathogen, Mycobacterium tuberculosis
(Mtb), requires IFN-γ. Although the adaptive immune response results in production of
substantial amounts of IFN-γ in response to Mtb, the immune response is unable to
eradicate the infection in most cases. We have previously reported evidence that Mtb inhibits
macrophage responses to IFN-γ, suggesting that this may limit the ability of IFN-γ to
stimulate macrophages to kill Mtb. We have also observed that uninfected macrophages …
Abstract
In humans and in mice, control of the intracellular pathogen, Mycobacterium tuberculosis (Mtb), requires IFN-γ. Although the adaptive immune response results in production of substantial amounts of IFN-γ in response to Mtb, the immune response is unable to eradicate the infection in most cases. We have previously reported evidence that Mtb inhibits macrophage responses to IFN-γ, suggesting that this may limit the ability of IFN-γ to stimulate macrophages to kill Mtb. We have also observed that uninfected macrophages, adjacent to infected macrophages in culture, exhibit decreased responses to IFN-γ. Here we report that IL-6 secreted by Mtb-infected macrophages inhibits the responses of uninfected macrophages to IFN-γ. IL-6 selectively inhibits a subset of IFN-γ-responsive genes at the level of transcriptional activation without inhibiting activation or function of STAT1. Inhibition of macrophage responses to IFN-γ by IL-6 requires new protein synthesis, but this effect is not attributable to suppressor of cytokine signaling 1 or 3. These results reveal a novel function for IL-6 and indicate that IL-6 secreted by Mtb-infected macrophages may contribute to the inability of the cellular immune response to eradicate infection.
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