IL-6 cytoprotection in hyperoxic acute lung injury occurs via suppressor of cytokine signaling-1-induced apoptosis signal-regulating kinase-1 degradation.
Hyperoxic acute lung injury (HALI) is characterized by a cell death response that is inhibited by IL-6. Suppressor of cytokine signaling-1 (SOCS-1) is an antiapoptotic negative regulator of the IL-6-mediated Janus kinase-signal transducer and activator of transcription signaling pathway. We hypothesized that SOCS-1 is a critical regulator and key mediator of IL-6-induced cytoprotection in HALI. To test this hypothesis, we characterized the expression of SOCS-1 and downstream apoptosis signal-regulating kinase (ASK)-1-Jun N-terminal kinase signaling molecules in small airway epithelial cells in the presence of H(2)O(2), which induces oxidative stress. We also examined these molecules in wild-type and lung-specific IL-6 transgenic (Tg(+)) mice exposed to 100% oxygen for 72 hours. In control small airway epithelial cells exposed to H(2)O(2) or in wild-type mice exposed to 100% oxygen, a marked induction of ASK-1 and pJun N-terminal kinase was observed. Both IL-6-stimulated endogenous SOCS-1 and SOCS-1 overexpression abolished H(2)O(2)-induced ASK-1 activation. In addition, IL-6 Tg(+) mice exposed to 100% oxygen exhibited reduced ASK-1 levels and enhanced SOCS-1 expression compared with wild-type mice. Interestingly, no significant changes in activation of the key ASK-1 activator, tumor necrosis factor receptor-1/tumor necrosis factor receptor-associated factor-2 were observed between wild-type and IL-6 Tg(+) mice. Furthermore, the interaction between SOCS-1 and ASK-1 promotes ubiquitin-mediated degradation both in vivo and in vitro. These studies demonstrate that SOCS-1 is an important regulator in IL-6-induced cytoprotection against HALI.
Kolliputi
Narasaiah
N
Pulmonary Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Bulfinch 148, Boston, MA 02114, USA.
Waxman
Aaron B
AB
D055371:Acute Lung Injury / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D019610:Cytoprotection / Q000502:physiology*; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D018496:Hyperoxia / Q000378:metabolism* / Q000473:pathology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D016877:Oxidants / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D053199:TNF Receptor-Associated Death Domain Protein / Q000235:genetics / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D014598:Uteroglobin / Q000235:genetics / Q000378:metabolism
D015850:Interleukin-6; D016877:Oxidants; D047888:Receptors, Tumor Necrosis Factor, Type I; C556389:SCGB1A1 protein, human; C556390:Scgb1a1 protein, mouse; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D053199:TNF Receptor-Associated Death Domain Protein; D047992:TNF Receptor-Associated Factor 2; C506236:Tnfrsf1a protein, mouse; C481226:Tradd protein, mouse; D014598:Uteroglobin; D006861:Hydrogen Peroxide; D048031:JNK Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse; D053181:Caspase 8
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