| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
,
Departments of
*
Medicine,
Anesthesiology, and
Biomolecular Chemistry, and
Comprehensive Cancer Center, University of Wisconsin Medical School, Madison, WI 53792
The nucleotide receptor P2X7 is expressed by most leukocytes and initiates signaling events that amplify numerous LPS responses. We tested the hypothesis that loss-of-function polymorphisms in the human P2X7 gene predispose to the production of an anti-inflammatory mediator balance. Accordingly, we developed a novel P2X7 pore assay in whole blood that magnifies the activity from wild-type alleles and preserves the gene dosage effect for the 1513 C polymorphism (AA, 69 ± 4; AC, 42 ± 4; and CC, 6 ± 1-fold stimulation). Thirty of 200 healthy individuals were identified as having low P2X7 pore activity. Seven low pore subjects were 1513 CC, 3 and 11 participants had the other known variants 946 GA and 1729 TA respectively; the remaining 9 volunteers likely have novel polymorphisms. Because platelets are a large source of extracellular ATP during inflammation, whole blood was treated ex vivo with Salmonella typhimurium LPS in the absence of exogenous nucleotides. LPS-stimulated whole blood from individuals in the low pore activity group generated reduced plasma levels of TNF-
(p = 0.036) and higher amounts of IL-10 (p < 0.001) relative to the high pore controls. This reduction in the TNF- to IL-10 ratio persisted to at least 24 h and is further decreased by cotreatment with 2-methylthio-ATP. The ability of P2X7 polymorphisms to regulate the LPS-induced TNF- to IL-10 ratio suggests that 15% of healthy adults may exhibit anti-inflammatory mediator responses during major infectious perturbations of the immune system, which can be predicted by P2X7 pore activity.
This article has been cited by other articles:
|
|
 |
|
  L. C. Denlinger, L. Shi, A. Guadarrama, K. Schell, D. Green, A. Morrin, K. Hogan, R. L. Sorkness, W. W. Busse, and J. E. Gern Attenuated P2X7 Pore Function as a Risk Factor for Virus-induced Loss of Asthma Control Am. J. Respir. Crit. Care Med., February 15, 2009; 179(4): 265 - 270. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. M. Kunzli, P. O. Berberat, T. Giese, E. Csizmadia, E. Kaczmarek, C. Baker, I. Halaceli, M. W. Buchler, H. Friess, and S. C. Robson Upregulation of CD39/NTPDases and P2 receptors in human pancreatic disease Am J Physiol Gastrointest Liver Physiol, January 1, 2007; 292(1): G223 - G230. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. C. Denlinger, D. B. Coursin, K. Schell, G. Angelini, D. N. Green, A. G. Guadarrama, J. Halsey, U. Prabhu, K. J. Hogan, and P. J. Bertics Human P2X7 Pore Function Predicts Allele Linkage Disequilibrium Clin. Chem., June 1, 2006; 52(6): 995 - 1004. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 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]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
