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This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 297/1/L6    most recent 90381.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Kolliputi, N. Articles by Waxman, A. B. PubMed PubMed Citation Articles by Kolliputi, N. Articles by Waxman, A. B.

IL-6 cytoprotection in hyperoxic acute lung injury occurs via PI3K/Akt-mediated Bax phosphorylation

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

Submitted 16 July 2008 ; accepted in final form 16 April 2009

IL-6 overexpression protects mice from hyperoxic acute lung injury in vivo, and treatment with IL-6 protects cells from oxidant-mediated death in vitro. The mechanisms of protection, however, are not clear. We characterized the expression, localization, and regulation of Bax, a proapoptotic member of the Bcl-2 family, in wild-type (WT) and IL-6 lung-specific transgenic (Tg⁺) mice exposed to 100% O₂ and in human umbilical vein endothelial cells (HUVEC) treated with H₂O₂ and IL-6. In control HUVEC treated with H₂O₂ or in WT mice exposed to 100% O₂, a marked induction of Bax translocation and dimerization was associated with increased JNK and p38 kinase activity. In contrast, specific JNK or p38 kinase inhibitors or treatment with IL-6 inhibited Bax mitochondrial translocation and apoptosis of HUVEC. IL-6 Tg⁺ mice exposed to 100% O₂ exhibited enhanced phosphatidylinositol 3-kinase (PI3K)/Akt kinase and increased serine phosphorylation of Bax at Ser¹⁸⁴ compared with WT mice. The PI3K-specific inhibitor LY-2940002 blocked this IL-6-induced Bax phosphorylation and promoted cell death. Furthermore, IL-6 potently blocked hyperoxia- or oxidant-induced Bax insertion into mitochondrial membranes. Thus IL-6 functions in a cytoprotective manner, in part, by suppressing Bax translocation and dimerization through PI3K/Akt-mediated Bax phosphorylation.

apoptosis; mitochondria; endothelial cells; JNK; cytokine; Bcl-2