Silencing suppressor of cytokine signaling-1 (SOCS1) in macrophages improves Mycobacterium tuberculosis control in an interferon-γ (IFN-γ)-dependent manner

Berit Carow, Xiang Qun Ye, Dolores Gavier-Wide, Sabin Bhuju, Wulf Oehlmann, Mahavir Singh, Markus Sköld, Lech Ignatowicz, Akihiko Yoshimura, Hans Wigzell, Martin E. Rottenberg

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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.

Original languageEnglish
Pages (from-to)26873-26887
Number of pages15
JournalJournal of Biological Chemistry
Volume286
Issue number30
DOIs
Publication statusPublished - 2011 Jul 29

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Carow, B., Ye, X. Q., Gavier-Wide, D., Bhuju, S., Oehlmann, W., Singh, M., Sköld, M., Ignatowicz, L., Yoshimura, A., Wigzell, H., & Rottenberg, M. E. (2011). Silencing suppressor of cytokine signaling-1 (SOCS1) in macrophages improves Mycobacterium tuberculosis control in an interferon-γ (IFN-γ)-dependent manner. Journal of Biological Chemistry, 286(30), 26873-26887. https://doi.org/10.1074/jbc.M111.238287