Interleukin-11 and interleukin-6 protect cultured human endothelial cells from H2O2-induced cell death.
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 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).
Waxman
Aaron B
AB
Pulmonary Critical Care Unit, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Bulfinch 148 Boston, MA 02114. ABWaxman@Partners.org
Mahboubi
Keyvan
K
Knickelbein
Roy G
RG
Mantell
Lin L
LL
Manzo
Nicholas
N
Pober
Jordan S
JS
Elias
Jack A
JA
D000975:Antioxidants / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004727:Endothelium / Q000187:drug effects* / Q000276:immunology / Q000503:physiopathology; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity*; D018496:Hyperoxia / Q000139:chemically induced* / Q000188:drug therapy / Q000276:immunology; D017370:Interleukin-11 / Q000276:immunology / Q000494:pharmacology*; D015850:Interleukin-6 / Q000276:immunology / Q000494:pharmacology*; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010100:Oxygen / Q000633:toxicity; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
D000975:Antioxidants; D004268:DNA-Binding Proteins; D017370:Interleukin-11; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D006861:Hydrogen Peroxide; D017346:Protein Serine-Threonine Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D010100:Oxygen