title: A critical role for SOCS3 in innate resistance to Toxoplasma gondii.
abstract: The innate and adaptive immune responses that confer resistance to the intracellular pathogen Toxoplasma gondii critically depend on IL-12 production, which drives interferon-γ (IFN-γ) expression. Certain cytokines can activate STAT3 and limit IL-12 production to prevent infection-associated immune pathology, but T. gondii also directly activates STAT3 to evade host immunity. We show that suppressor of cytokine signaling molecule 3 (SOCS3), a target of STAT3 that limits signaling by the pleiotropic cytokine IL-6, is upregulated in response to infection but is dispensable for the immune-inhibitory effects of T. gondii. Unexpectedly, mice with targeted deletion of SOCS3 in macrophages and neutrophils have reduced IL-12 responses and succumb to toxoplasmosis. Anti-IL-6 administration or IL-12 treatment blocked disease susceptibility, suggesting that in the absence of SOCS3, macrophages are hypersensitive to the anti-inflammatory properties of IL-6. Thus, SOCS3 has a critical role in suppressing IL-6 signals and promoting immune responses to control T. gondii infection.
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, USA.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Whitmarsh
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Gray
authors.forename: Beth
authors.initials: B
authors.lastname: Gregg
authors.forename: David A
authors.initials: DA
authors.lastname: Christian
authors.forename: Michael J
authors.initials: MJ
authors.lastname: May
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Murray
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Hunter
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D018664:Interleukin-12 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000469:parasitology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000276:immunology*; D014122:Toxoplasma / Q000276:immunology* / Q000502:physiology; D014123:Toxoplasmosis / Q000235:genetics / Q000276:immunology* / Q000469:parasitology
chemical_list: D015850:Interleukin-6; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D018664:Interleukin-12