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Departments of
* Antibacterials, Immunology, and Inflammation and
Drug Safety Evaluation, Pfizer Global Research and Development, Pfizer Inc., Groton, CT 06340
When challenged with extracellular ATP, leukocytes respond and
activate processes attributed to the P2X7 receptor
(P2X7R), an unusual ligand-gated ion channel. To prove
P2X7R involvement, blood samples from
P2X7R-deficient mice were characterized. Monocytes and
lymphocytes associated with wild-type blood responded to ATP and
underwent volume/shape changes and shed L-selectin. In contrast,
leukocytes from P2X7R-deficient animals demonstrated no
change in physical properties or L-selectin expression following ATP
challenge. Blood stimulated with LPS or ATP individually generated
minimal quantities of the leaderless polypeptide IL-1
, but
sequential treatment of wild-type, but not P2X7R-deficient,
blood with LPS and ATP yielded large amounts of cell-free cytokine.
Based on these differences, wild-type and P2X7R-deficient
animals were compared following induction of monoclonal
anti-collagen-induced arthritis. Ab-treated wild-type animals
subsequently challenged with LPS developed inflamed, swollen paws;
their joint cartilage demonstrated lesions, loss of proteoglycan
content, and the presence of collagen degradation products.
P2X7R-deficient animals subjected to the same challenge
were markedly less affected; both the incidence and severity of disease
were reduced. These data indicate that ATP does act via the
P2X7R to affect leukocyte function and that the
P2X7R can serve as an important component of an in vivo
inflammatory response.
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Y.-H. Feng, X. Li, L. Wang, L. Zhou, and G. I. Gorodeski A Truncated P2X7 Receptor Variant (P2X7-j) Endogenously Expressed in Cervical Cancer Cells Antagonizes the Full-length P2X7 Receptor through Hetero-oligomerization J. Biol. Chem., June 23, 2006; 281(25): 17228 - 17237. [Abstract] [Full Text] [PDF]
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D. Ferrari, C. Pizzirani, E. Adinolfi, R. M. Lemoli, A. Curti, M. Idzko, E. Panther, and F. Di Virgilio The P2X7 Receptor: A Key Player in IL-1 Processing and Release J. Immunol., April 1, 2006; 176(7): 3877 - 3883. [Abstract] [Full Text] [PDF]
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L. Chen and C. F. Brosnan Exacerbation of Experimental Autoimmune Encephalomyelitis in P2X7R-/- Mice: Evidence for Loss of Apoptotic Activity in Lymphocytes. J. Immunol., March 1, 2006; 176(5): 3115 - 3126. [Abstract] [Full Text] [PDF]
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H. Kawamura, F. Aswad, M. Minagawa, S. Govindarajan, and G. Dennert P2X7 Receptors Regulate NKT Cells in Autoimmune Hepatitis J. Immunol., February 15, 2006; 176(4): 2152 - 2160. [Abstract] [Full Text] [PDF]
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A. N. Shemon, R. Sluyter, S. L. Fernando, A. L. Clarke, L.-P. Dao-Ung, K. K. Skarratt, B. M. Saunders, K. S. Tan, B. J. Gu, S. J. Fuller, et al. A Thr357 to Ser Polymorphism in Homozygous and Compound Heterozygous Subjects Causes Absent or Reduced P2X7 Function and Impairs ATP-induced Mycobacterial Killing by Macrophages J. Biol. Chem., January 27, 2006; 281(4): 2079 - 2086. [Abstract] [Full Text] [PDF]
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P. A. Verhoef, S. B. Kertesy, K. Lundberg, J. M. Kahlenberg, and G. R. Dubyak Inhibitory Effects of Chloride on the Activation of Caspase-1, IL-1{beta} Secretion, and Cytolysis by the P2X7 Receptor J. Immunol., December 1, 2005; 175(11): 7623 - 7634. [Abstract] [Full Text] [PDF]
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F. Aswad, H. Kawamura, and G. Dennert High Sensitivity of CD4+CD25+ Regulatory T Cells to Extracellular Metabolites Nicotinamide Adenine Dinucleotide and ATP: A Role for P2X7 Receptors J. Immunol., September 1, 2005; 175(5): 3075 - 3083. [Abstract] [Full Text] [PDF]
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G. Grutz New insights into the molecular mechanism of interleukin-10-mediated immunosuppression J. Leukoc. Biol., January 1, 2005; 77(1): 3 - 15. [Abstract] [Full Text] [PDF]
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D. Ferrari, C. Pizzirani, E. Adinolfi, S. Forchap, B. Sitta, L. Turchet, S. Falzoni, M. Minelli, R. Baricordi, and F. Di Virgilio The Antibiotic Polymyxin B Modulates P2X7 Receptor Function J. Immunol., October 1, 2004; 173(7): 4652 - 4660. [Abstract] [Full Text] [PDF]
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J. I. Elliott and C. F. Higgins Major Histocompatibility Complex Class I Shedding and Programmed Cell Death Stimulated Through the Proinflammatory P2X7 Receptor: A Candidate Susceptibility Gene for NOD Diabetes Diabetes, August 1, 2004; 53(8): 2012 - 2017. [Abstract] [Full Text] [PDF]
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H. L. Wilson, S. E. Francis, S. K. Dower, and D. C. Crossman Secretion of Intracellular IL-1 Receptor Antagonist (Type 1) Is Dependent on P2X7 Receptor Activation J. Immunol., July 15, 2004; 173(2): 1202 - 1208. [Abstract] [Full Text] [PDF]
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J. A. Sim, M. T. Young, H.-Y. Sung, R. A. North, and A. Surprenant Reanalysis of P2X7 Receptor Expression in Rodent Brain J. Neurosci., July 14, 2004; 24(28): 6307 - 6314. [Abstract] [Full Text] [PDF]
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 J. M. Kahlenberg and G. R. Dubyak Mechanisms of caspase-1 activation by P2X7 receptor-mediated K+ release Am J Physiol Cell Physiol, May 1, 2004; 286(5): C1100 - C1108. [Abstract] [Full Text] [PDF]
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R. Sluyter, A. N. Shemon, and J. S. Wiley Glu496 to Ala Polymorphism in the P2X7 Receptor Impairs ATP-Induced IL-1{beta} Release from Human Monocytes J. Immunol., March 15, 2004; 172(6): 3399 - 3405. [Abstract] [Full Text] [PDF]
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L. Gudipaty, J. Munetz, P. A. Verhoef, and G. R. Dubyak Essential role for Ca2+ in regulation of IL-1{beta} secretion by P2X7 nucleotide receptor in monocytes, macrophages, and HEK-293 cells Am J Physiol Cell Physiol, August 1, 2003; 285(2): C286 - C299. [Abstract] [Full Text] [PDF]
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 H. Z. Ke, H. Qi, A. F. Weidema, Q. Zhang, N. Panupinthu, D. T. Crawford, W. A. Grasser, V. M. Paralkar, M. Li, L. P. Audoly, et al. Deletion of the P2X7 Nucleotide Receptor Reveals Its Regulatory Roles in Bone Formation and Resorption Mol. Endocrinol., July 1, 2003; 17(7): 1356 - 1367. [Abstract] [Full Text] [PDF]
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S. M. Joseph, M. R. Buchakjian, and G. R. Dubyak Colocalization of ATP Release Sites and Ecto-ATPase Activity at the Extracellular Surface of Human Astrocytes J. Biol. Chem., June 20, 2003; 278(26): 23331 - 23342. [Abstract] [Full Text] [PDF]
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P. A. Verhoef, M. Estacion, W. Schilling, and G. R. Dubyak P2X7 Receptor-Dependent Blebbing and the Activation of Rho-Effector Kinases, Caspases, and IL-1{beta} Release J. Immunol., June 1, 2003; 170(11): 5728 - 5738. [Abstract] [Full Text] [PDF]
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R. E. Laliberte, D. G. Perregaux, L. R. Hoth, P. J. Rosner, C. K. Jordan, K. M. Peese, James. F. Eggler, M. A. Dombroski, K. F. Geoghegan, and C. A. Gabel Glutathione S-Transferase Omega 1-1 Is a Target of Cytokine Release Inhibitory Drugs and May Be Responsible for Their Effect on Interleukin-1beta Posttranslational Processing J. Biol. Chem., May 2, 2003; 278(19): 16567 - 16578. [Abstract] [Full Text] [PDF]
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J. S. Wiley, L.-P. Dao-Ung, C. Li, A. N. Shemon, B. J. Gu, M. L. Smart, S. J. Fuller, J. A. Barden, S. Petrou, and R. Sluyter An Ile-568 to Asn Polymorphism Prevents Normal Trafficking and Function of the Human P2X7 Receptor J. Biol. Chem., May 2, 2003; 278(19): 17108 - 17113. [Abstract] [Full Text] [PDF]
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G. R. Dubyak Knock-Out Mice Reveal Tissue-Specific Roles of P2Y Receptor Subtypes in Different Epithelia Mol. Pharmacol., April 1, 2003; 63(4): 773 - 776. [Full Text] [PDF]
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S. Duan, C. M. Anderson, E. C. Keung, Y. Chen, Y. Chen, and R. A. Swanson P2X7 Receptor-Mediated Release of Excitatory Amino Acids from Astrocytes J. Neurosci., February 15, 2003; 23(4): 1320 - 1328. [Abstract] [Full Text] [PDF]
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R. Sluyter and J. S. Wiley Extracellular adenosine 5'-triphosphate induces a loss of CD23 from human dendritic cells via activation of P2X7 receptors Int. Immunol., December 1, 2002; 14(12): 1415 - 1421. [Abstract] [Full Text] [PDF]
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S. Adriouch, C. Dox, V. Welge, M. Seman, F. Koch-Nolte, and F. Haag Cutting Edge: A Natural P451L Mutation in the Cytoplasmic Domain Impairs the Function of the Mouse P2X7 Receptor J. Immunol., October 15, 2002; 169(8): 4108 - 4112. [Abstract] [Full Text] [PDF]
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