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Genetic ablation of PI3K? results in defective IL-17RA signalling in T lymphocytes and increased IL-17 levels

Harris, Stephanie J., Ciuclan, Loredana, Finan, Peter M., Wymann, Matthias P., Walker, Christoph, Westwick, John, Ward, Stephen G. and Thomas, Matthew J. 2012. Genetic ablation of PI3K? results in defective IL-17RA signalling in T lymphocytes and increased IL-17 levels. European Journal of Immunology 42 (12) , pp. 3394-3404. 10.1002/eji.201242463

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Abstract

The signalling molecule PI3Kγ has been reported to play a key role in the immune system and the inflammatory response. In particular, it facilitates the migration of haemato‐poietic cells to the site of inflammation. In this study, we reveal a novel role for PI3Kγ in the regulation of the pro‐inflammatory cytokine IL‐17. Loss of PI3Kγ or expression of a catalytically inactive mutant of PI3Kγ in mice led to increased IL‐17 production both in vitro and in vivo in response to various stimuli. The kinetic profile was unaltered from WT cells, with no effect on proliferation or other cytokines. Elevated levels of IL‐17 were not due to an aberrant expansion of IL‐17‐producing cells. Furthermore, we also identified an increase in IL‐17RA expression on PI3Kγ−/− CD4+ T cells, yet these cells exhibited impaired PI3K‐dependent signalling in response to IL‐17A, and subsequent NF‐κB phosphorylation. In vivo, instillation of recombinant IL‐17 into the airways of mice lacking PI3Kγ signalling also resulted in reduced phosphorylation of Akt. Cell influx in response to IL‐17 was also reduced in PI3Kγ−/− lungs. These data demonstrate PI3Kγ‐dependent signalling downstream of IL‐17RA, which plays a pivotal role in regulating IL‐17 production in T cells.

Item Type: Article
Date Type: Publication
Status: Published
Publisher: John Wiley & Sons
ISSN: 0014-2980
Date of Acceptance: 21 August 2012
Last Modified: 12 Mar 2020 11:08
URI: http://orca-mwe.cf.ac.uk/id/eprint/130345

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