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IL‐6 Inhibits Hyperoxia Induced Bax Translocation Through Pi3kinase/AKT Mediated Bax Phosphorylation
Author(s) -
Kolliputi Narasaiah V,
Meloney Laura G,
Kathryn Steiner M,
Waxman Aaron B
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1238.4
Subject(s) - hyperoxia , apoptosis , protein kinase b , phosphorylation , p38 mitogen activated protein kinases , chemistry , chromosomal translocation , programmed cell death , microbiology and biotechnology , kinase , cancer research , biology , mapk/erk pathway , biochemistry , oxygen , gene , organic chemistry
We have shown that IL‐6 over expression protects mice from hyperoxic acute lung injury (HALI) in vivo and treatment with IL‐6 protects against oxidant mediated cell death in vitro. However, the mechanisms to account for these findings are not yet known. We hypothesized that Bax, a pro‐apoptotic member of Bcl‐2 family, may play an important role in oxidant mediated cell death and that IL‐6 may block this pathway. We characterized the expression, and localization of Bax and its regulation in WT and IL‐6 lung specific over expression transgenic (IL‐6 Tg(+)) mice exposed to 100% oxygen for 72 hours in vivo. We also analyzed the same proteins in HUVEC with and without H 2 O 2 in the presence or absence of IL‐6. In control HUVEC treated with H 2 O 2 , or WT mice exposed to 100% oxygen, there was marked induction of Bax translocation and dimirization associated with increased pJNK and p38kinase activity. In contrast, 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, have reduced pJNK, p38 levels, enhanced Pi3kinase/AKT kinase, and increased serine phosphorylation of Bax compared with WT mice. Moreover IL‐6 treated cells or S184 transfected cells have increased Bax phosphorylation and decreased translocation. IL‐6 potently blocks either hyperoxia or oxidant‐induced Bax insertion intomitochondrial membranes. We concluded that IL‐6 is cytoprotective, in part, by suppressing Bax translocation and dimirization through Pi3kinase/AKT mediated Bax phosphorylation. This work is supported by NIH grant RO1HL074859 to Waxman A.B and NIH training grant 5 T32 HL 007874‐12 to Steiner M. K.