title: Nucleotide receptor P2RX7 stimulation enhances LPS-induced interferon-β production in murine macrophages.
abstract: Stimulation of P2RX(7) with extracellular ATP potentiates numerous LPS-induced proinflammatory events, including cytokine induction in macrophages, but the molecular mechanisms underlying this process are not well defined. Although P2RX(7) ligation has been proposed to activate several transcription factors, many of the LPS-induced mediators affected by P2RX(7) activation are not induced by P2RX(7) agonists alone, suggesting a complementary role for P2RX(7) in transcriptional regulation. Type I IFN production, whose expression is tightly controlled by multiple transcription factors that form an enhanceosome, is critical for resistance against LPS-containing bacteria. The effect of purinergic receptor signaling on LPS-dependent type I IFN is unknown and would be of great relevance to a diverse array of inflammatory conditions. The present study demonstrates that stimulation of macrophages with P2RX(7) agonists substantially enhances LPS-induced IFN-β expression, and this enhancement is ablated in macrophages that do not express functional P2RX(7) or when the MAPK MEK1/2 pathways are inhibited. Potentiation of LPS-induced IFN-β expression following P2RX(7) stimulation is likely transcriptionally regulated, as this enhancement is observed at the IFN-β promoter level. Furthermore, P2RX(7) stimulation is able to increase the phosphorylation and subsequent IFN-β promoter occupancy of IRF-3, a transcription factor that is critical for IFN-β transcription by TLR agonists. This newly discovered role for P2RX(7) in IFN regulation may have implications in antimicrobial defense, which has been linked to P2RX(7) activation in other studies.
authors.affiliation: 2.University of Wisconsin School of Medicine and Public Health, 600 Highland Ave., CSC H4/472, Madison, WI 53792-9988, USA. jsmith27@pediatrics.wisc.edu.
authors.forename: M L
authors.initials: ML
authors.lastname: Gavala
authors.forename: Y-P
authors.initials: YP
authors.lastname: Liu
authors.forename: L Y
authors.initials: LY
authors.lastname: Lenertz
authors.forename: L
authors.initials: L
authors.lastname: Zeng
authors.forename: J B
authors.initials: JB
authors.lastname: Blanchette
authors.forename: A G
authors.initials: AG
authors.lastname: Guadarrama
authors.forename: L C
authors.initials: LC
authors.lastname: Denlinger
authors.forename: P J
authors.initials: PJ
authors.lastname: Bertics
authors.forename: J A
authors.initials: JA
authors.lastname: Smith
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D016899:Interferon-beta / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009711:Nucleotides / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D058911:Purinergic P2X Receptor Agonists / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*
chemical_list: C483819:Fosb protein, mouse; D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; D008070:Lipopolysaccharides; D009711:Nucleotides; D016760:Proto-Oncogene Proteins c-fos; D058911:Purinergic P2X Receptor Agonists; D012333:RNA, Messenger; D058486:Receptors, Purinergic P2X7; C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; D016899:Interferon-beta; D000255:Adenosine Triphosphate; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: IRF-3; endotoxin; enhanceosome; extracellular ATP; type I IFN
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