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.
Mesh Terms:
Acute Lung Injury, Animals, Caspase 8, Cells, Cultured, Cytoprotection, Epithelial Cells, Humans, Hydrogen Peroxide, Hyperoxia, Interleukin-6, JNK Mitogen-Activated Protein Kinases, MAP Kinase Kinase Kinase 5, Mice, Mice, Transgenic, Oxidants, Receptors, Tumor Necrosis Factor, Type I, Signal Transduction, Suppressor of Cytokine Signaling Proteins, TNF Receptor-Associated Death Domain Protein, TNF Receptor-Associated Factor 2, Uteroglobin
Acute Lung Injury, Animals, Caspase 8, Cells, Cultured, Cytoprotection, Epithelial Cells, Humans, Hydrogen Peroxide, Hyperoxia, Interleukin-6, JNK Mitogen-Activated Protein Kinases, MAP Kinase Kinase Kinase 5, Mice, Mice, Transgenic, Oxidants, Receptors, Tumor Necrosis Factor, Type I, Signal Transduction, Suppressor of Cytokine Signaling Proteins, TNF Receptor-Associated Death Domain Protein, TNF Receptor-Associated Factor 2, Uteroglobin
Am. J. Respir. Cell Mol. Biol.
Date: Mar. 01, 2009
PubMed ID: 18776134
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