Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 560, Issue 2-3, Pages 101-109Publisher
ELSEVIER
DOI: 10.1016/j.ejphar.2007.01.025
Keywords
Akt; HO-1 [heme oxygenase-1]; human lung epithelial cell; NF-kappa B [nuclear factor-kappa B]; PI3K [phosphoinositide-3-OH-kinase]; TGF+beta 1 [transforming growth factor-beta 1]
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A previous report showed that transforming growth factor+beta 1 (TGF+beta 1) can induce heme oxygenase-1 (HO-1) expression, attenuate cellular injury, and maintain tissue homeostasis. In this study, we investigated the involvement of phosphoinositide-3-OH-kinase (PI3K)/Akt and the nuclear factor-kappa B (NF-kappa B) signaling pathway in TGF-beta 1-induced HO-1 expression in human lung epithelial cells (A549). Treatment of A549 cells with TGF-beta 1 caused HO-1 to be expressed in a concentration- and time-dependent manner. Treatment of A549 cells with LY 294002 (2-(4-morpholinyl)-8-phenyl-4H- 1-benzopyran-4-one, a PI3K inhibitor), an Akt inhibitor, and the dominant negative mutant of Akt (Akt DN) inhibited TGF-beta 1-induced HO-1 expression and HO-1-luciferase activity. Stimulation of cells with TGF-beta 1 caused an increase in Akt phospborylation in a time-dependent manner, which was inhibited by wortmannin and LY 294002 (PI3K inhibitors). In addition, treatment of A549 cells with Bay 117082 ((E)-3-[4-methylphenylsulfonyt]-2-propenenitrile, an I kappa B phosphorylation inhibitor), pyrrolidine dithiocarbamate (PDTC, an NF-kappa B inhibitor), and the dominant negative mutant of I kappa B alpha (I kappa B alpha M) inhibited TGF-beta 1-induced HO-I expression and HO-1-luciferase activity. Treatment of A549 cells with TGF-beta 1-induced I kappa B kinase alpha/beta (IKK alpha/beta) phosphorylation, IKBa phosphorylation, I kappa B alpha degradation, p65 Ser536 phosphorylation, and kappa B-luciferase activity. The TGF-beta 1-mediated increases in IKK alpha/beta phosphorylation, p65 Ser536 phosphorylation, and kappa B-luciferase activity were inhibited by LY 294002, an Akt inhibitor, and Akt DN. Taken together, these results suggest that the PI3K/Akt dependent IKK alpha/beta/NF-kappa B signaling pathway plays an important role in TGF-beta 1-induced HO-1 expression in A549 cells. (c) 2007 Elsevier B.V. All rights reserved.
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