Regulation of tristetraprolin expression by interleukin-1β and dexamethasone in human pulmonary epithelial cells: Roles for nuclear factor-κB and p38 mitogen-activated protein kinase

King, Elizabeth M. and Kaur, Manminder and Gong, Wei and Rider, Christopher F. and Holden, Neil S. and Newton, Robert (2009) Regulation of tristetraprolin expression by interleukin-1β and dexamethasone in human pulmonary epithelial cells: Roles for nuclear factor-κB and p38 mitogen-activated protein kinase. The journal of pharmacology and experimental therapeutics, 330 (2). pp. 575-585. ISSN 0022-3565

Full content URL: http://jpet.aspetjournals.org/content/330/2/575

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Regulation of tristetraprolin expression by interleukin-1β and dexamethasone in human pulmonary epithelial cells: Roles for nuclear factor-κB and p38 mitogen-activated protein kinase

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Abstract

The mRNA-destabilizing protein tristetraprolin (TTP) negatively regulates adenine- and uridine-rich element (ARE)-containing mRNAs. In A549 pulmonary cells, TTP mRNA and both a approximately 40- and a approximately 45-kDa phosphorylated version of TTP protein were rapidly induced in response to interleukin (IL)-1beta. Analysis with IkappaBalphaDeltaN, a dominant version of inhibitor of kappaBalpha (IkappaBalpha), as well as dominant-negative and small-molecule IkappaB kinase (IKK) inhibitors demonstrated that IL-1beta-induced TTP is nuclear factor-kappaB (NF-kappaB)-dependent. Likewise, TTP expression and formation of the approximately 45-kDa phosphorylated form of TTP are blocked by the p38 mitogen-activated protein kinase (MAPK) inhibitor 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580). By contrast, and despite a 3- to 4-fold induction of TTP mRNA, the anti-inflammatory glucocorticoid dexamethasone only modestly induced expression of the approximately 40-kDa form of TTP. In the context of IL-1beta, dexamethasone exerted a marginal repressive effect on TTP mRNA expression and more considerably reduced TTP protein. Given a requirement for p38 MAPK in the induction of TTP by IL-1beta, this repressive effect may be explained by repression of the p38 MAPK pathway by dexamethasone. Knockdown of TTP protein by siRNA elevated IL-1beta-induced expression of granulocyte macrophage-colony-stimulating factor (GM-CSF) and IL-8, demonstrating a role for TTP in feedback control. Likewise, knockdown of TTP increased GM-CSF expression in the presence of IL-1beta plus dexamethasone, suggesting that feedback control by TTP also occurs in the context of IL-1beta plus dexamethasone. Taken together, our data demonstrate that NF-kappaB and p38 MAPK are critical to the induction of TTP by IL-1beta and that TTP induction provides feedback control of the ARE-containing genes GM-CSF and IL-8.

Keywords:dexamethasones, gene expression regulation, interleukin 1beta, NF-kappa B, p38 Mitogen-Activated Protein Kinases, respiratory mucosa, tristetrapolin
Subjects:B Subjects allied to Medicine > B210 Pharmacology
Divisions:College of Science > School of Life Sciences
ID Code:15123
Deposited On:19 Nov 2014 14:44

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