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Genetic ablation of PI3Kgamma results in defective IL-17RA signalling in T lymphocytes and increased IL-17 levels

Harris, S. J. and Ciuclan, L. and Finan, P. M. and Wymann, M. P. and Walker, C. and Westwick, J. and Ward, S. G. and Thomas, M. J.. (2012) Genetic ablation of PI3Kgamma results in defective IL-17RA signalling in T lymphocytes and increased IL-17 levels. European journal of immunology, Vol. 42, H. 12. pp. 3394-3404.

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Official URL: http://edoc.unibas.ch/dok/A6338015

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Abstract

The signalling molecule PI3Kgamma 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 PI3Kgamma in the regulation of the pro-inflammatory cytokine IL-17. Loss of PI3Kgamma or expression of a catalytically inactive mutant of PI3Kgamma 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 PI3Kgamma(-/-) CD4(+) T cells, yet these cells exhibited impaired PI3K-dependent signalling in response to IL-17A, and subsequent NF-kappaB phosphorylation. In vivo, instillation of recombinant IL-17 into the airways of mice lacking PI3Kgamma signalling also resulted in reduced phosphorylation of Akt. Cell influx in response to IL-17 was also reduced in PI3Kgamma(-/-) lungs. These data demonstrate PI3Kgamma-dependent signalling downstream of IL-17RA, which plays a pivotal role in regulating IL-17 production in T cells.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Division of Biochemistry and Genetics > Cancer- and Immunobiology (Wymann)
UniBasel Contributors:Wymann, Matthias P.
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Verl. Chemie
ISSN:0014-2980
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:10 Apr 2015 09:13
Deposited On:10 Apr 2015 09:13

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