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Activation of phosphatidylinositol 3-kinase by interleukin-13 - An inhibitory signal for inducible nitric-oxide synthase expression in the epithelial, cell line HT-29.

Wright, Karen and Ward, Stephen G. and Kolios, George and Westwick, John (1997) Activation of phosphatidylinositol 3-kinase by interleukin-13 - An inhibitory signal for inducible nitric-oxide synthase expression in the epithelial, cell line HT-29. Journal of Biological Chemistry, 272. pp. 12626-12633.

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Abstract

The human colonic epithelial cell line HT-29 can be induced by a combination of the cytokines interleukin (IL)-1α, tumor necrosis factor α, and interferon-γ to express the inducible form of nitric-oxide synthase (iNOS; Kolios, G., Brown, Z., Robson, R., Robertson, D. A. F., & Westwick, J. (1995) Br. J. Pharmacol.116, 2866–2872). IL-13 is a potent inhibitor of cytokine-induced iNOS mRNA expression and nitric oxide generation in HT-29 cells via an unknown mechanism. We report here that in HT-29 cells, IL-13 induces a concentration and time-dependent increase in the formation of the lipid products of phosphatidylinositol (PtdIns) 3-kinase, namely phosphatidylinositol (3,4)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate. IL-13 also induces a parallel concentration and time-dependent increase in thein vitro lipid kinase activity present in immunoprecipitates of the p85 regulatory subunit of PtdIns 3-kinase. In addition, we also demonstrate that IL-13 stimulates the tyrosine phosphorylation of the adaptor molecule insulin receptor substrate 1, which may facilitate receptor coupling to PtdIns 3-kinase. Both the increases in D-3 phosphatidylinositol lipids and the increased in vitro lipid kinase activity of p85 immunoprecipitates were inhibited by wortmannin and LY294002. Inhibition of the PtdIns 3-kinase activity was paralleled by a reversal of the ability of IL-13 to inhibit iNOS mRNA expression and nitrite generation in HT-29 cells. These data demonstrate that the activation of PtdIns 3-kinase by IL-13 is a key signal that is responsible for the inhibition of iNOS transcription in activated epithelial cells.

Item Type: Article
Journal or Publication Title: Journal of Biological Chemistry
Subjects: R Medicine > RM Therapeutics. Pharmacology
Departments: Faculty of Health and Medicine > Biomedical & Life Sciences
ID Code: 40900
Deposited By: Mr Richard Ingham
Deposited On: 16 Jun 2011 13:11
Refereed?: Yes
Published?: Published
Last Modified: 26 Jul 2012 18:06
Identification Number:
URI: http://eprints.lancs.ac.uk/id/eprint/40900

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