Submitted on July 16, 2008
Revised on April 13, 2009
Accepted on April 16, 2009
IL-6 Cytoprotection In Hyperoxic Acute Lung Injury Occurs Via Pi3 Kinase/Akt-Mediated Bax Phosphorylation
Narasaiah Kolliputi1 and Aaron B Waxman1*
1 Massachusetts General Hospital
* To whom correspondence should be addressed. E-mail: abwaxman{at}partners.org.
Interleukin-6 (IL-6) overexpression protects mice from hyperoxic acute lung injury (HALI) 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% oxygen 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% oxygen, a marked induction of Bax translocation and dimerization was associated with increased c-Jun N-terminal kinase (pJNK) 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 cells. IL-6 Tg(+) mice exposed to 100% oxygen exhibited enhanced phosphoinositide 3 kinase (PI3K)/AKT kinase and increased serine phosphorylation of Bax at Ser184 compared with WT mice. The PI3K specific inhibitor LY2940002 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.
