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Interleukin-11 and Interleukin-6 Protect Cultured Human Endothelial Cells from H₂O₂-Induced Cell Death

Pulmonary Critical Care Unit, Massachusetts General Hospital, Boston, Massachusetts; Interdepartmental Program in Vascular Biology and Transplantation, Boyer Center for Molecular Medicine, Yale University School of Medicine; Department of Pediatrics, Yale University School of Medicine, Department of Internal Medicine, New Haven, Connecticut; Cardiac Research Laboratory, Department of Surgery, North Shore-Long Island Jewish Medical Center, New York University School of Medicine, Manhasset, New York; and Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, Department of Internal Medicine, New Haven, Connecticut

Address correspondence to: Aaron B. Waxman, Pulmonary Critical Care Unit, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Bulfinch 148 Boston, MA 02114. E-mail: ABWaxman{at}Partners.org

Acute lung injury is a frequent and treatment-limiting consequence of therapy with 100% oxygen. Previous studies have determined that both interleukin (IL)-6 and IL-11 are protective in oxygen toxicity. This protection was associated with markedly diminished alveolar–capillary protein leak, endothelial and epithelial membrane injury, lipid peroxidation, and pulmonary neutrophil recruitment. Hyperoxia also caused cell death with DNA fragmentation in the lungs of transgene (-) animals, and both IL-6 and IL-11 markedly diminished this cell death response. However, the mechanism(s) by which these cytokines protect cells from death is unclear. In the present study, we characterized the effects of H₂O₂ on subconfluent human umbilical vein endothelial cell (HUVEC) and human pulmonary microvascular endothelial cell (HPMEC) cultures. We found that preincubation of HUVEC cultures with either IL-6 or IL-11 diminished H₂O₂ (1.0 mM)-induced cell death. Similar effects were noted with HPMEC showing that this effect is not HUVEC-specific. The protective effects of both IL-6 and IL-11 were not associated with any changes in antioxidants and were decreased by 80% in the presence of U0126, a specific inhibitor of MEK-1–dependent pathways. The cytoprotective effects of IL-11 and IL-6 were also completely eliminated in STAT3 dominant-negative transduced HUVEC cultures. These studies demonstrate that IL-6 and IL-11 both confer cytoprotective effects that diminish oxidant-mediated endothelial cell injury. They also demonstrate that this protection is mediated, at least in part, by a STAT3 and MEK-1–dependent specific signal transduction pathway(s).

Abbreviations: human pulmonary microvascular endothelial cell(s), HPMEC • horseradish peroxidase, HRP • human umbilical vein endothelial cell(s), HUVEC • interleukin, IL • polyacrylamide gel electrophoresis, PAGE • phosphate-buffered saline, PBS • sodium dodecyl sulfate, SDS • superoxide dismutase, SOD

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