The P2X7 loss-of-function Glu496Ala polymorphism affects ex vivo cytokine release and protects against the cytotoxic effects of high ATP-levels

BMC Immunology

Pieter C Dagnelie¹  Piet Geusens⁴  Esther HE Theunisz²  Ilja CW Arts¹  Martijn JL Bours³  Anke Wesselius³ 

[1] Department of Epidemiology, Maastricht University, School for Cardiovascular Diseases (CARIM), Maastricht, The Netherlands;Department of Toxicology, Maastricht University Medical Centre School for Public Health and Primary Care (CAPHRI), Maastricht, The Netherlands;Department of Epidemiology, Maastricht University, School for Public Health and Primary Care (CAPHRI), Peter Debyeplein 1, Maastricht, MD, 6200, The Netherlands;Department of Internal Medicine, Subdivision of Rheumatology Maastricht University Medical Center, P. O. Box 5800, Maastricht, 6202 AZ, The Netherlands

关键词: Inflammation;    Polymorphism;    P2X₇;    ATP;   

Others  :  1077862
DOI  :  10.1186/1471-2172-13-64

 received in 2012-07-18, accepted in 2012-11-23,  发布年份 2012

【 摘 要 】

Background

The P2X₇ receptor plays an important role in cytokine release during the inflammatory response in vivo. Polymorphisms within the P2X₇ receptor gene that lead to loss of receptor function may contribute to impaired cytokine release by immune cells. Therefore, we investigated whether a known loss-of-function polymorphism (Glu496Ala) in the P2X₇ receptor gene leads to alterations in cytokine release in response to ATP.

Results

An ex vivo whole blood model was used to induce an inflammatory reaction with the pro-inflammatory stimuli LPS and PHA (phytohemagglutinin). Blood from n=9 subjects with the Glu496Ala P2X7 SNP (P2X7MUT) and n=7 ‘wild-type’ subjects (no P2X7 SNP; P2X7WT) was used.

Addition of ATP (0.9-3 mM) to LPS/PHA-stimulated whole blood induced an increase in IL-1β release in P2X7MUT subjects, whereas decreased release was observed in P2X7WT subjects. Decreased levels of IL-6 and TNF-α in response to ATP were shown in both P2X7MUT and P2X7WT subjects, which was less pronounced in P2X7MUT subjects. ATP at 3 mM also significantly decreased levels of lactate dehydrogenase (LDH) in P2X7MUT subjects compared to P2X7WT subjects.

Conclusions

The presence of the non-synonymous Glu496Ala loss-of-function polymorphism within the P2X₇ receptor gene is likely to be of importance in the release of cytokines during inflammation. Furthermore, this study suggests that carriers of the Glu496Ala loss-of-function polymorphism are protected against the cytotoxic effects of high ATP-levels.

【 授权许可】

   
2012 Wesselius et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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