| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Secretion, and Cytolysis by the P2X7 Receptor1
,
* Department of Physiology and Biophysics,
Department of Pharmacology, and
Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106
The P2X7 receptor (P2X7R) is an ATP-gated cation channel that activates caspase-1 leading to the maturation and secretion of IL-1
. Because previous studies indicated that extracellular Cl– exerts a negative allosteric effect on ATP-gating of P2X7R channels, we tested whether Cl– attenuates the P2X7R
caspase-1IL-1 signaling cascade in murine and human macrophages. In Bac1 murine macrophages, substitution of extracellular Cl– with gluconate produced a 10-fold increase in the rate and extent of ATP-induced IL-1 processing and secretion, while reducing the EC50 for ATP by 5-fold. Replacement of Cl– with gluconate also increased the potency of ATP as an inducer of mature IL-1 secretion in primary mouse bone marrow-derived macrophages and in THP-1 human monocytes/macrophages. Our observations were consistent with actions of Cl– at three levels: 1) a negative allosteric effect of Cl–, which limits the ability of ATP to gate the P2X7R-mediated cation fluxes that trigger caspase-1 activation; 2) an intracellular accumulation of Cl– via nonselective pores induced by P2X7R with consequential repression of caspase-1-mediated processing of IL-1; and 3) a facilitative effect of Cl– substitution on the cytolytic release of unprocessed pro-IL-1 that occurs with sustained activation of P2X7R. This cytolysis was repressed by the cytoprotectant glycine, permitting dissociation of P2X7R-regulated secretion of mature IL-1 from the lytic release of pro-IL-1. These results suggest that under physiological conditions P2X7R are maintained in a conformationally restrained state that limits channel gating and coupling of the receptor to signaling pathways that regulate caspase-1.
This article has been cited by other articles:
|
|
 |
|
  S. Hong, N. Schwarz, A. Brass, M. Seman, F. Haag, F. Koch-Nolte, W. P. Schilling, and G. R. Dubyak Differential Regulation of P2X7 Receptor Activation by Extracellular Nicotinamide Adenine Dinucleotide and Ecto-ADP-Ribosyltransferases in Murine Macrophages and T Cells J. Immunol., July 1, 2009; 183(1): 578 - 592. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Qu, L. Ramachandra, S. Mohr, L. Franchi, C. V. Harding, G. Nunez, and G. R. Dubyak P2X7 Receptor-Stimulated Secretion of MHC Class II-Containing Exosomes Requires the ASC/NLRP3 Inflammasome but Is Independent of Caspase-1 J. Immunol., April 15, 2009; 182(8): 5052 - 5062. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Roger, P. Pelegrin, and A. Surprenant Facilitation of P2X7 Receptor Currents and Membrane Blebbing via Constitutive and Dynamic Calmodulin Binding J. Neurosci., June 18, 2008; 28(25): 6393 - 6401. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Takenouchi, Y. Iwamaru, S. Sugama, M. Sato, M. Hashimoto, and H. Kitani Lysophospholipids and ATP Mutually Suppress Maturation and Release of IL-1{beta} in Mouse Microglial Cells Using a Rho-Dependent Pathway J. Immunol., June 15, 2008; 180(12): 7827 - 7839. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. C. Rupper and J. A. Cardelli Induction of Guanylate Binding Protein 5 by Gamma Interferon Increases Susceptibility to Salmonella enterica Serovar Typhimurium-Induced Pyroptosis in RAW 264.7 Cells Infect. Immun., June 1, 2008; 76(6): 2304 - 2315. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Pelegrin, C. Barroso-Gutierrez, and A. Surprenant P2X7 Receptor Differentially Couples to Distinct Release Pathways for IL-1{beta} in Mouse Macrophage J. Immunol., June 1, 2008; 180(11): 7147 - 7157. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Allantaz, D. Chaussabel, D. Stichweh, L. Bennett, W. Allman, A. Mejias, M. Ardura, W. Chung, C. Wise, K. Palucka, et al. Blood leukocyte microarrays to diagnose systemic onset juvenile idiopathic arthritis and follow the response to IL-1 blockade J. Exp. Med., September 3, 2007; 204(9): 2131 - 2144. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Qu, L. Franchi, G. Nunez, and G. R. Dubyak Nonclassical IL-1beta Secretion Stimulated by P2X7 Receptors Is Dependent on Inflammasome Activation and Correlated with Exosome Release in Murine Macrophages J. Immunol., August 1, 2007; 179(3): 1913 - 1925. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Tsukimoto, M. Maehata, H. Harada, A. Ikari, K. Takagi, and M. Degawa P2X7 Receptor-Dependent Cell Death Is Modulated during Murine T Cell Maturation and Mediated by Dual Signaling Pathways. J. Immunol., September 1, 2006; 177(5): 2842 - 2850. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
