title: IL-6 promotes acute and chronic inflammatory disease in the absence of SOCS3.
abstract: The lack of expression of the suppressor of cytokine signalling-3 (SOCS3) or inactivation of the negative regulatory capacity of SOCS3 has been well documented in rheumatoid arthritis, viral hepatitis and cancer. The specific qualitative and quantitative consequences of SOCS3 deficiency on interleukin-6 (IL-6)-mediated pro- and anti-inflammatory responses remain controversial in vitro and unknown in vivo. Mice with a conditional deletion of SOCS3 in hematopoietic cells develop lethal inflammatory disease during adult life and develop gross histopathological changes during experimental arthritis, typified by elevated IL-6 levels. To clarify the nature of the IL-6 responses in vivo, we generated mice deficient in SOCS3 (SOCS3(-/Δvav)) or both SOCS3 and IL-6 (IL-6(-/-)/SOCS3(-/Δvav)), and examined responses in models of acute and chronic inflammation. Acute responses to IL-1β were lethal to SOCS3(-/Δvav) mice but not IL-6(-/-)/SOCS3(-/Δvav) mice, indicating that IL-6 was required for the lethal inflammation induced by IL-1β. Administration of IL-1β to SOCS3(-/Δvav) mice induced systemic apoptosis of lymphocytes in the thymus, spleen and lymph nodes that was dependent on the presence of IL-6. IL-6 deficiency prolonged survival of SOCS3(-/Δvav) mice and ameliorated spontaneous inflammatory disease developing during adult life. Infection of SOCS3(-/Δvav) mice with LCMV induced a lethal inflammatory response that was dependent on IL-6, despite SOCS3(-/Δvav) mice controlling viral replication. We conclude that SOCS3 is required for survival during inflammatory responses and is a critical regulator of IL-6 in vivo.
authors.affiliation: Department of Inflammation, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. croker@wehi.edu.au
authors.forename: Ben A
authors.initials: BA
authors.lastname: Croker
authors.forename: Hiu
authors.initials: H
authors.lastname: Kiu
authors.forename: Marc
authors.initials: M
authors.lastname: Pellegrini
authors.forename: Jesse
authors.initials: J
authors.lastname: Toe
authors.forename: Simon
authors.initials: S
authors.lastname: Preston
authors.forename: Donald
authors.initials: D
authors.lastname: Metcalf
authors.forename: Joanne A
authors.initials: JA
authors.lastname: O'Donnell
authors.forename: Louise H
authors.initials: LH
authors.lastname: Cengia
authors.forename: Kate
authors.initials: K
authors.lastname: McArthur
authors.forename: Nicos A
authors.initials: NA
authors.lastname: Nicola
authors.forename: Warren S
authors.initials: WS
authors.lastname: Alexander
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Roberts
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002908:Chronic Disease; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008216:Lymphocytic Choriomeningitis / Q000276:immunology / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000276:immunology*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D016019:Survival Analysis
chemical_list: D016207:Cytokines; D053583:Interleukin-1beta; D015850:Interleukin-6; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins