Silencing suppressor of cytokine signaling-1 (SOCS1) in macrophages improves Mycobacterium tuberculosis control in an interferon-gamma (IFN-gamma)-dependent manner |
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Authors: | Carow Berit Ye Xiang qun Gavier-Widén Dolores Bhuju Sabin Oehlmann Wulf Singh Mahavir Sköld Markus Ignatowicz Lech Yoshimura Akihiko Wigzell Hans Rottenberg Martin E |
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Affiliation: | Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm 17177, Sweden. |
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Abstract: | Protection against infection with Mycobacterium tuberculosis demands IFN-γ. SOCS1 has been shown to inhibit responses to IFN-γ and might thereby play a central role in the outcome of infection. We found that M. tuberculosis is a highly efficient stimulator of SOCS1 expression in murine and human macrophages and in tissues from infected mice. Surprisingly, SOCS1 reduced responses to IL-12, resulting in an impaired IFN-γ secretion by macrophages that in turn accounted for a deteriorated intracellular mycobacterial control. Despite SOCS1 expression, mycobacteria-infected macrophages responded to exogenously added IFN-γ. SOCS1 attenuated the expression of the majority of genes modulated by M. tuberculosis infection of macrophages. Using a conditional knockdown strategy in mice, we found that SOCS1 expression by macrophages hampered M. tuberculosis clearance early after infection in vivo in an IFN-γ-dependent manner. On the other hand, at later time points, SOCS1 expression by non-macrophage cells protected the host from infection-induced detrimental inflammation. |
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Keywords: | Bacteria Immunology Inflammation Interferon Macrophages Interleukins SOCS Tuberculosis |
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