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IL-6 Cytoprotection in Hyperoxic Acute Lung Injury Occurs via Suppressor of Cytokine Signaling-1–Induced Apoptosis Signal–Regulating Kinase-1 Degradation

¹ Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

Correspondence and requests for reprints should be addressed to Aaron B. Waxman, MD, Ph.D., Pulmonary Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Bulfinch 148, Boston, MA 02114. E-mail: abwaxman{at}Partners.org

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 H₂O₂, 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 H₂O₂ 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 H₂O₂-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.

Key Words: IL-6 • apoptosis signal–regulating kinase-1 • suppressor of cytokine signaling-1 • lung injury • tumor necrosis factor receptor-1

CLINICAL RELEVANCE These studies demonstrate, for the first time, that IL-6–induced protection against hyperoxic acute lung injury works through suppressor of cytokine signaling-1–induced apoptosis signal–regulating kinase-1 ubiquitin-mediated degradation.

 

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