CD39 is a negative regulator of P2X7-mediated inflammatory cell death in mast cells

Cell Communication and Signaling

Research

Marco Idzko¹  Cemil Korcan Ayata¹  Michael Huber²  Thomas Hochdörfer²  Marcel Kuhny² 

[1] Department of Pneumology, University Medical Center, Killianstraße 5, 79106, Freiburg, Germany;Institute of Biochemistry and Molecular Immunology, University Clinic, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany;

关键词: ATP;    BMMC;    CD39;    Cell death;    IL-1β;    P2X7;   

DOI  :  10.1186/s12964-014-0040-3

 received in 2014-04-03, accepted in 2014-06-13,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundMast cells (MCs) are major contributors to an inflammatory milieu. One of the most potent drivers of inflammation is the cytokine IL-1β, which is produced in the cytoplasm in response to danger signals like LPS. Several controlling mechanisms have been reported which limit the release of IL-1β. Central to this regulation is the NLRP3 inflammasome, activation of which requires a second danger signal with the capacity to subvert the homeostasis of lysosomes and mitochondria. High concentrations of extracellular ATP have the capability to perturb the plasma membrane by activation of P2X7 channels and serve as such a danger signal. In this study we investigate the role of P2X7 channels and the ecto-5´-nucleotidase CD39 in ATP-triggered release of IL-1β from LPS-treated mast cells.ResultsWe report that in MCs CD39 sets an activation threshold for the P2X7-dependent inflammatory cell death and concomitant IL-1β release. Knock-out of CD39 or stimulation with non-hydrolysable ATP led to a lower activation threshold for P2X7-dependent responses. We found that stimulation of LPS-primed MCs with high doses of ATP readily induced inflammatory cell death. Yet, cell death-dependent release of IL-1β yielded only minute amounts of IL-1β. Intriguingly, stimulation with low ATP concentrations augmented the production of IL-1β in LPS-primed MCs in a P2X7-independent but caspase-1-dependent manner.ConclusionOur study demonstrates that the fine-tuned interplay between ATP and different surface molecules recognizing or modifying ATP can control inflammatory and cell death decisions.

【 授权许可】

Unknown   
© Kuhny et al.; licensee Biomed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.