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Background  The  P2X   7   receptor plays an important role in cytokine release during the inflammatory response  in vivo.  Polymorphisms within the  P2X   7   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  P2X   7   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  P2X   7   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.

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