title: Silencing suppressor of cytokine signaling-1 (SOCS1) in macrophages improves Mycobacterium tuberculosis control in an interferon-gamma (IFN-gamma)-dependent manner.
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.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm 17177, Sweden.
authors.forename: Berit
authors.initials: B
authors.lastname: Carow
authors.forename: Xiang qun
authors.initials: Xq
authors.lastname: Ye
authors.forename: Dolores
authors.initials: D
authors.lastname: Gavier-Widén
authors.forename: Sabin
authors.initials: S
authors.lastname: Bhuju
authors.forename: Wulf
authors.initials: W
authors.lastname: Oehlmann
authors.forename: Mahavir
authors.initials: M
authors.lastname: Singh
authors.forename: Markus
authors.initials: M
authors.lastname: Sköld
authors.forename: Lech
authors.initials: L
authors.lastname: Ignatowicz
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
authors.forename: Hans
authors.initials: H
authors.lastname: Wigzell
authors.forename: Martin E
authors.initials: ME
authors.lastname: Rottenberg
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D020868:Gene Silencing; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009169:Mycobacterium tuberculosis / Q000276:immunology / Q000378:metabolism*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014376:Tuberculosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: C108944:SOCS1 protein, human; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D018664:Interleukin-12; D007371:Interferon-gamma