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

Elizabeth M. King, Manminder Kaur, Wei Gong, Christopher F. Rider, Neil S. Holden, Robert Newton

    Research output: Contribution to journalArticlepeer-review

    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 ∼40-and a ∼45-kDa phosphorylated version of TTP protein were rapidly induced in response to interleukin (IL)-1β. Analysis with IκBαΔN, a dominant version of inhibitor of κBα (IκBα), as well as dominant-negative and small-molecule IκB kinase (IKK) inhibitors demonstrated that IL-1β-induced TTP is nuclear factor-κB (NF-κB)-dependent. Likewise, TTP expression and formation of the ∼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 ∼40-kDa form of TTP. In the context of IL-1β, 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-1β, this repressive effect may be explained by repression of the p38 MAPK pathway by dexamethasone. Knockdown of TTP protein by siRNA elevated IL-1β-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-1β plus dexamethasone, suggesting that feedback control by TTP also occurs in the context of IL-1β plus dexamethasone. Taken together, our data demonstrate that NF-κB and p38 MAPK are critical to the induction of TTP by IL-1β and that TTP induction provides feedback control of the ARE-containing genes GM-CSF and IL-8. Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics.
    Original languageEnglish
    Pages (from-to)575-585
    Number of pages10
    JournalJournal of Pharmacology and Experimental Therapeutics
    Volume330
    Issue number2
    DOIs
    Publication statusPublished - Aug 2009

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