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Published ahead of print on May 1, 2003, doi:10.1165/rcmb.2002-0044OC

Am. J. Respir. Cell Mol. Biol., Volume 29, Number 4, October 2003, 513-522

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Submitted on April 9, 2002
Revised on April 30, 2003

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

Aaron B Waxman1*, Keyvan Mahboubi2, Roy G Knickelbein3, Lin L Mantell4, Nicholas Manzo1, Jordan S Pober2, and Jack A Elias5

1 Pulmonary Critical Care, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA, 2 Pathology, Yale School of Medicine, New Haven, CT, USA, 3 Pediatrics, Yale School of Medicine, New Haven, CT, USA, 4 Cardio-Pulmonary Research Institute, Winthrop University Hospital, Mineola, NY, USA, 5 Pulmonary Critical Care, Yale School of Medicine, New Haven, CT, USA

* To whom correspondence should be addressed. 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 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 sub-confluent 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 (1.0mM) 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 approximately 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).




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