Abstract
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% O(2) and in human umbilical vein endothelial cells (HUVEC) treated with H(2)O(2) and IL-6. In control HUVEC treated with H(2)O(2) or in WT mice exposed to 100% O(2), 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% O(2) exhibited enhanced phosphatidylinositol 3-kinase (PI3K)/Akt kinase and increased serine phosphorylation of Bax at Ser(184) 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.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
Acute Lung Injury / complications
-
Acute Lung Injury / enzymology*
-
Acute Lung Injury / pathology
-
Animals
-
Apoptosis / drug effects
-
Cytoprotection / drug effects*
-
Endothelial Cells / cytology
-
Endothelial Cells / drug effects
-
Endothelial Cells / enzymology
-
Enzyme Activation / drug effects
-
Gene Silencing / drug effects
-
Humans
-
Hydrogen Peroxide / pharmacology
-
Hyperoxia / complications*
-
Hyperoxia / enzymology
-
Hyperoxia / pathology
-
Interleukin-6 / pharmacology*
-
JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
-
Mice
-
Mitochondrial Membranes / drug effects
-
Mitochondrial Membranes / metabolism
-
Organ Specificity / drug effects
-
Oxidants / pharmacology
-
Phosphatidylinositol 3-Kinases / metabolism*
-
Phosphorylation / drug effects
-
Phosphoserine / metabolism
-
Protein Kinase Inhibitors / pharmacology
-
Protein Multimerization / drug effects
-
Protein Transport / drug effects
-
Proto-Oncogene Proteins c-akt / metabolism*
-
Stress, Physiological / drug effects
-
bcl-2-Associated X Protein / metabolism*
-
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
Substances
-
Interleukin-6
-
Oxidants
-
Protein Kinase Inhibitors
-
bcl-2-Associated X Protein
-
Phosphoserine
-
Hydrogen Peroxide
-
Phosphatidylinositol 3-Kinases
-
Proto-Oncogene Proteins c-akt
-
JNK Mitogen-Activated Protein Kinases
-
p38 Mitogen-Activated Protein Kinases