title: Suppressor of cytokine signaling-1 regulates the sensitivity of pancreatic beta cells to tumor necrosis factor.
abstract: Suppressor of cytokine signaling-1 (SOCS-1) is a negative regulator of the Jak-STAT (signal transducer and activator of transcription cytokine) signaling pathway but may also regulate other pathways. At least in vitro, SOCS-1 inhibits the action of multiple cytokines. By studying the effects of SOCS-1 deficiency, we investigated whether SOCS-1 is involved in preventing cytokine-induced death of pancreatic islet cells, a potential mechanism of insulin deficiency in autoimmune diabetes. Tumor necrosis factor (TNF) + interferon-gamma (IFNgamma) was more potent at inducing cell death in SOCS-1-/- islets than in wild type. Individually, these cytokines did not induce cell death. The titration of the two cytokines suggested that this increased cell death was because of hypersensitivity to TNF. Interleukin-1 + IFNgamma induced the same level of cell death in SOCS-1-/- and wild-type islets, suggesting that the sensitivity of islets to IFNgamma or interleukin-1-mediated cytotoxicity is not affected by SOCS-1 deficiency. Additionally, SOCS-1-/- beta cells were responsive to lower concentrations of TNF measured by class I major histocompatibility complex up-regulation. The TNF + IFNgamma damage of islets was mediated by inducible nitric-oxide synthase (iNOS), and increased iNOS expression and nitric oxide production were found in SOCS-1-/- islets following cytokine treatment. A further analysis revealed that SOCS-1 deficiency results in augmented TNF signaling via the p38 mitogen-activated protein kinase pathway but not NFkappaB or c-Jun N-terminal kinase pathways. Increased p38 signaling may be responsible for the increased iNOS expression in SOCS-1-/- islets. Therefore, these findings provide evidence that physiological levels of SOCS-1 negatively regulate TNF signaling.
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Post Office Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.
authors.forename: Mark M W
authors.initials: MM
authors.lastname: Chong
authors.forename: Helen E
authors.initials: HE
authors.lastname: Thomas
authors.forename: Thomas W H
authors.initials: TW
authors.lastname: Kay
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D012097:Repressor Proteins; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D007375:Interleukin-1; D012097:Repressor Proteins; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse