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BRIEF REVIEWS |
* Department of Experimental and Diagnostic Medicine, Section of General Pathology, and
Interdisciplinary Center for the Study of Inflammation, University of Ferrara, Ferrara, Italy;
Institute of Haematology and Medical Oncology "L. & A. Seragnoli," University of Bologna, Bologna, Italy; and
Department of Pneumology, University of Freiburg, Freiburg, Germany.
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Abstract |
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 Top Abstract IntroductionIL-1IL-1RaIL-18The P2X7R for extracellular...The P2X7R and IL-1...P2X7R activation by...P2X7R-dependent secretion of...IL-1 and ATP as...PerspectivesReferences |
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Introduction |
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TopAbstractIntroductionIL-1IL-1RaIL-18The P2X7R for extracellular...The P2X7R and IL-1...P2X7R activation by...P2X7R-dependent secretion of...IL-1 and ATP as...PerspectivesReferences |
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is a key mediator of host response to infections and a primary cause of inflammation (1, 2). Bacterial products (e.g., LPS) and host-derived inflammatory factors cause the synthesis of IL-1 in the form of a biologically inactive procytokine (molecular mass, 31 kDa) that remains dispersed in the cytosol until a second stimulus drives processing and release of the 17-kDa active form. IL-1
and IL-18, two additional members of the IL-1 superfamily with proinflammatory activity, are also synthesized as leaderless procytokines and accumulate in the cell cytoplasm in the absence of a maturation-promoting second stimulus (1, 3). Another member of the IL-1 superfamily, IL-1 receptor antagonist (IL-1Ra),3 is also synthesized and released in parallel to IL-1, IL-1, and IL-18 (4). IL-1Ra binds to type I IL-1 receptor (IL-1RI) and blocks IL-1-dependent signal transduction, thus functioning as an endogenous, IL-1-selective inhibitor of inflammation (5).
In vivo, IL-1 is elevated during infections and in several chronic inflammatory diseases such as arthritis, scleroderma, systemic lupus erythematosus, vasculitis, sepsis, septic shock, and in the presence of atherosclerotic lesions leading to myocardial infarction (2). However, the in vitro process of IL-1 release is very inefficient, as activated monocytes release into the extracellular space < 10% of the IL-1 accumulated intracellularly (6). This finding has led to postulate that IL-1 release requires two stimuli (two hits), the first one driving gene transcription and pro-IL-1 accumulation and the second one processing and release.
In recent years, increasing attention has been paid to extracellular ATP as a candidate danger signal locally released at the inception of inflammation (7, 8). One of the most striking features of this nucleotide is its unmatched ability to promote massive release of mature IL- from LPS-primed mononuclear phagocytes and other cell types (9). ATP-driven maturation and release of IL-1 are specifically mediated by the P2X7 receptor (P2X7R) for extracellular ATP (10, 11, 12). The molecular dissection of this novel pathway for cytokine release may disclose new targets for anti-inflammatory therapy.
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IL-1 |
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TopAbstractIntroductionIL-1IL-1RaIL-18The P2X7R for extracellular...The P2X7R and IL-1...P2X7R activation by...P2X7R-dependent secretion of...IL-1 and ATP as...PerspectivesReferences |
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IL-1 and IL-1 share low sequence homology (20–30%) but high three-dimensional similarity. Upon cell activation, typically via plasma membrane TLRs, IL-1 and IL-1 are translated as 31-kDa leaderless secretory proteins (pro-IL-1 and pro-IL-1). Although IL-1 is already active in this form, IL-1 needs a proteolytical step to generate the 17-kDa mature cytokine. Pro-IL-1 can be processed in the extracellular milieu by several proteases activated during inflammation, whereas the IL-1-converting enzyme, later named caspase (casp)-1, is the key protease responsible for intracellular IL-1 processing (15, 16). Recently, IL-33, an IL-1-like cytokine acting at the ST2 receptor, has also been shown to be processed by casp-1 (17). In resting cells, casp-1 is normally present as an inactive 45-kDa precursor, procaspase (procasp)-1. Proteolytical activation of procasp-1 occurs in a multimeric specialized structure named "IL-1 inflammasome protein complex" (18) comprising at least four different proteins (casp-1, casp-5, apoptosis-associated speck-like protein containing a CARD (ASC), and NACHT-, LRR-, and PYD-containing protein) that transiently oligomerize upon cell activation (19). The mechanism of inflammasome assembly and activation is a focus of intense investigation.
IL-1 and IL-1 bind to the same receptor named IL-1RI. Upon IL-1 binding, IL-1RI recruits the accessory protein IL-1R-AcP, a member of the Ig superfamily, and initiates a stimulatory signal transduction cascade. A decoy receptor is also present, IL-1RII, that is unable to complex with IL-1R-AcP and to generate a biological signal (20). IL-1RII competes with IL-1RI to down-modulate IL-1 activity (21).
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IL-1Ra |
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TopAbstractIntroductionIL-1IL-1RaIL-18The P2X7R for extracellular...The P2X7R and IL-1...P2X7R activation by...P2X7R-dependent secretion of...IL-1 and ATP as...PerspectivesReferences |
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The IL-1Ra knockout mouse spontaneously develops diseases similar to human rheumatoid arthritis and arteritis (24, 25). Administration of anakinra, a recombinant form of IL-1Ra, reduces local inflammation of joints and bone erosions in patients with rheumatoid arthritis (26, 27).
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IL-18 |
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TopAbstractIntroductionIL-1IL-1RaIL-18The P2X7R for extracellular...The P2X7R and IL-1...P2X7R activation by...P2X7R-dependent secretion of...IL-1 and ATP as...PerspectivesReferences |
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, IL-18 is not an endogenous pyrogen (2). IL-18 binds to an heterodimeric receptor inducing the synthesis of other proinflammatory cytokines (IL-6, IL-8, TNF-, IL-1, and IFN-
), CD95 ligand, and several chemokines. It also increases the expression of ICAM-1 and VCAM-1 on endothelial cells (2). IL-18 is secreted by a variety of cells, including epithelial cells, keratinocytes, synovial fibroblasts, monocytes, macrophages, and dendritic cells (DCs) (30). Like IL-1, IL-18 behaves as an angiogenic factor through increased expression of vascular endothelial growth factor. |
The P2X7R for extracellular ATP |
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TopAbstractIntroductionIL-1IL-1RaIL-18The P2X7R for extracellular...The P2X7R and IL-1...P2X7R activation by...P2X7R-dependent secretion of...IL-1 and ATP as...PerspectivesReferences |
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-pleated sheets (37). This region has been proposed to host the ATP binding site (38). The main structural distinctive feature of the P2X7R is a long C-terminal tail (244 aa) harboring multiple potential protein and lipid interaction motifs (see Fig. 1) (39). Although other receptors of the P2X subfamily have been shown to form functional hetero-oligomers, the P2X7 subunits seem to associate only with each other to form homomeric P2X7R (40). Unique in the P2XR subfamily, P2X7R is highly polymorphic. More than 260 single nucleotide polymorphisms (SNPs) have been described in the human P2X7R gene, but only a few have been functionally characterized. Wiley and coworkers (41, 42, 43) have identified four loss-of-function single amino acid substitutions, three located in the cytoplasmic tail of the receptor (T357S, E496A, and I568N), and one in the putative ATP binding site (R307Q) (38). Our group has characterized the first gain-of-function polymorphism so far identified (H155Y) (44). Wiley and coworkers (45) have also described a splice site mutation in the first intron of the P2X7R gene that produces a null allele. Polymorphisms in the promoter region of the gene have also been identified (46). No convincing disease association has been so far demonstrated for these SNPs.
The mechanism of pore formation by the P2X7R is a matter of debate: while some investigators hold the conservative opinion that pore formation is due to an ATP-dependent increase in size of the P2X7R channel itself (47), others believe that the pore is a separate molecular structure activated by the P2X7R (48, 49). Early studies by Dubyak and coworkers (48, 49) suggested that it might coincide with the plasma membrane pore activated by the sea toxin maitotoxin. More recently, Elliott et al. (50) have hypothesized that P2X7R-dependent transitions in plasma membrane permeability might involve the modulation of the multidrug transporter P-glycoprotein. Whichever the molecular basis of pore formation, there is no doubt that P2X7R activation causes a massive upset of cytoplasmic ion homeostasis (51). Because the P2X7R is nondesensitizing, the pore stays open as long it is bound by ATP. Removal of the nucleotide, by rinsing or apyrase-catalyzed hydrolysis, causes pore closure, thus allowing a reversible plasma membrane permeabilization. Should ATP stimulation be prolonged (over 15–30 min in most cell types), the cells become irreversibly injured and committed to death (52).
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The P2X7R and IL-1 release |
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TopAbstractIntroductionIL-1IL-1RaIL-18The P2X7R for extracellular...The P2X7R and IL-1...P2X7R activation by...P2X7R-dependent secretion of...IL-1 and ATP as...PerspectivesReferences |
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in the cytosol while acting as only a very weak stimulator of IL-1 maturation and externalization (6). This has led investigators to postulate a second stimulus to trigger efficient IL-1 conversion and release. Early observations showed that extracellular ATP was a strong IL-1-releasing agent (53, 54, 55). Although at that time the identity of the plasma membrane receptor(s) involved and the signal transduction cascade activated was unknown, the massive efflux of intracellular K+ triggered by extracellular ATP suggested a mechanism based on cytoplasmic K+ depletion (51, 54, 56). Experiments performed in vitro and in vivo in P2X7R –/– mice conclusively identified the receptor responsible for ATP-dependent IL-1 release as the P2X7R (10, 11, 12, 57, 58).
The ATP effect is very fast, as externalization of mature IL-1 is near maximal within 10–20 min. The main IL-1 released form is the 17 kDa, but sustained ATP stimulation can also cause release of the 31-kDa form and of cytoplasmic markers suggestive of a late nonspecific damage of the plasma membrane (11, 54). However, if care is taken to use ATP concentrations in the 0.5–1 mM range and short incubation times (15 min), a selective release of mature IL-1 occurs and cells fully recover from the ATP challenge (11). Furthermore, it has been shown that cell lysis per se is unable to support pro-IL-1 conversion (59).
It is currently debated whether extracellular ATP needs LPS priming to activate casp-1. Although until recently it was thought that priming was unnecessary (60, 61), two novel studies suggest that LPS pretreatment might indeed be needed to achieve substantial generation of casp-1 activation fragments in mouse macrophages (62, 63). Furthermore, blockade by YVAD-CHO shows that casp-1 activity is necessary for P2X7R-dependent release of mature IL-1 (Refs.60 and 61 but see Ref.64). The role of K+ efflux in supporting P2X7R-dependent IL-1 processing and release seems to be crucial as both processes are suppressed by inhibition of intracellular K+ efflux (11, 54, 61, 65, 66). Conversely, release of IL-1 is enhanced in sucrose-containing medium, a condition in which K+ efflux is strongly potentiated (11, 61). Incidentally and in further support of the view that P2X7R-dependent IL-1 secretion does not require cell lysis, in sucrose medium, ATP-stimulated release of cytoplasmic markers is negligible (11, 67). Mutations in the human P2X7R that prevent pore formation and reduce ATP-stimulated K+ efflux (e.g., the E496A substitution) inhibit IL-1 release (35). Interestingly, this inhibitory effect is more marked in isolated macrophages than in whole blood (68), suggesting that in the presence of blood cells additional stimulatory factors are released. Altogether, there is consensus that the drastic upset of K+ homeostasis caused by P2X7R opening has a key role in triggering IL-1 maturation, whereas other intracellular ions (e.g., Ca2+) seem to be more involved in IL-1 release (66, 69). This view is also supported by the casp-1 activating effect of nigericin-induced K+ depletion (70). A recent article (62) by Dixit’s laboratory shows that mice deficient in the adaptor protein ASC fail to process pro-IL-1 in response to ATP, thus suggesting that P2X7R-dependent casp-1 cleavage may require assembly of a fully functional inflammasome. How the change in intracellular K+ concentration drives this process is an open question. On the other hand, a direct physical interaction of the P2X7R with the inflammasome is as yet undocumented.
IL-1 is a leaderless protein that does not appear to be contained within classical exocytotic vesicles. Thus, how it is externalized has long been a mystery. In the last few years experiments by Rubartelli and coworkers (66) and Surprenant and colleagues (71) have shed light on this issue suggesting a vesicular mechanism (Fig. 2). However, there are two crucial differences in the pathways proposed by the two groups: Rubartelli suggests that IL-1 is accumulated into endocytic vesicles (secretory lysosomes) together with casp-1, then a P2X7R-induced loss of intracellular K+ activates phosphatidylcholine-specific phospholipase C, which in turn causes an increase in cytosolic Ca2+, Ca2+-dependent phospholipase A2 activation, and exocytosis of the IL-1-containing lysosomes. According to this model, casp-1 activation and IL-1 processing are triggered by the K+ loss-stimulated activation of a Ca2+-independent phospholipase A2 within the lysosomes.
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is packaged into small plasma membrane blebs that are released into the extracellular space as microvesicles of size ranging from 200 nm to 1 mm. These microvesicles are akin to the tissue factor-containing microparticles released from various cell types (72) and different from the large plasma membrane blebs that are also produced in cells stimulated via the P2X7R (71, 73). Microvesicle budding and release are preceded by phosphatidylserine flip and loss of membrane asymmetry (71), a change in the membrane phospholipid structure that might have a relevant signaling function (50). Recent experiments have shown that a vesicle-mediated mechanism for IL-1 release is also present in mouse microglia and human DCs (Ref.74 ; C. Pizzirani and F. Di Virgilio, submitted for publication). In DCs, casp-1 and -3 are also loaded into the vesicles, thus providing a mechanism for intravesicular pro-IL-1 processing.
The microvesicle model proposed by Surprenant raises an obvious criticism: how does mature IL-1 get through the microvesicle membrane and reaches the extracellular space to activate IL-1Rs? Recent observations from Verderio’s laboratory and from our own group provide a possible answer: microvesicles shed from microglia and DCs, express the P2X7R (together with several other markers), and lyse when exposed to extracellular ATP (Ref.74 ; C. Pizzirani and F. Di Virgilio, submitted for publication). Thus, it can be hypothesized that once the microvesicles approach the plasma membrane of the target cells, where the ATP concentration is higher than in the bulk solution due to active cellular release (75), the P2X7R is activated, the microvesicles lyse, and IL-1 is released. In both the Rubartelli and Surprenant models, P2X7R activation is crucial, but how and if this receptor is activated under physiological conditions is as yet an open question.
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P2X7R activation by extracellular ligands |
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TopAbstractIntroductionIL-1IL-1RaIL-18The P2X7R for extracellular...The P2X7R and IL-1...P2X7R activation by...P2X7R-dependent secretion of...IL-1 and ATP as...PerspectivesReferences |
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release via P2X7R, but it is likely that this needs priming with ATP (76, 77). Since the cytoplasmic ATP concentration is in the millimolar range, acute cell injury or death will cause massive ATP release into the extracellular milieu. However, there is compelling evidence for nonlytic ATP secretion via as yet unidentified pathways activated by host- or pathogen-derived factors (76, 78, 79, 80, 81). Measurements performed with membrane-bound probes in platelets, human neuroblastoma cells, and P2X7R-transfected HEK293 cells show that the ATP concentration at the plasma membrane surface is much higher than in the bulk solution and may range from 20 to 200 µm (75, 82). This suggests that ATP levels sufficient to activate the P2X7R may be reached in the pericellular space. In addition, proinflammatory cytokines or bacterial products up-regulate P2X7R expression and increase its sensitivity to extracellular ATP (83, 84, 85). In principle, pericellular ATP levels can also be increased by ecto-ATPase inhibition. It has been recently shown that Abs raised against a surface expressed ATPase known as regeneration and tolerance factor potentiate ATP-stimulated IL-1 release from macrophages (86). In mouse, but not in human, thymocytes ADP-ribosylation due to extracellular NAD can also activate the P2X7R, although it is not clear whether this mechanism is operative in macrophages (87). More recently, an antimicrobial peptide derived from human cathelicidin (LL37) was reported to directly activate the P2X7R and trigger IL-1 secretion (80). Thus, it is likely that as our knowledge of the P2X7R expands, we will find additional physiologically relevant ligands for this receptor. |
P2X7R-dependent secretion of other IL-1 family members |
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TopAbstractIntroductionIL-1IL-1RaIL-18The P2X7R for extracellular...The P2X7R and IL-1...P2X7R activation by...P2X7R-dependent secretion of...IL-1 and ATP as...PerspectivesReferences |
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, as with IL-1, is retained mostly within the cytoplasm unless extracellular ATP is added (88). Stimulation of IL-1 release occurs via the P2X7R and follows a time course similar to that of IL-1. Both pro-IL-1 and mature IL-1 are released. The physiological meaning of P2X7R-dependent pro-IL-1 cleavage is not clear because this cytokine, in contrast to pro-IL-1, is a full agonist at IL-1Rs.
In response to ATP, macrophages and endothelial cells (HUVECs) also release IL-1Ra. In macrophages, but not in HUVECs, release occurs via P2X7R-stimulated microvesicle release (89). In monocytes, P2X7R-stimulated release of IL-18 occurs with a time course similar to that of IL-1, requires priming with LPS, and is prevented by the P2X7R E496A loss-of-function polymorphism (64, 90).
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IL-1 and ATP as danger signals |
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TopAbstractIntroductionIL-1IL-1RaIL-18The P2X7R for extracellular...The P2X7R and IL-1...P2X7R activation by...P2X7R-dependent secretion of...IL-1 and ATP as...PerspectivesReferences |
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Perspectives |
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TopAbstractIntroductionIL-1IL-1RaIL-18The P2X7R for extracellular...The P2X7R and IL-1...P2X7R activation by...P2X7R-dependent secretion of...IL-1 and ATP as...PerspectivesReferences |
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or IL-1RI Abs, rIL-1Ra or IL-1Trap). Now, the many points of control of IL-1 synthesis, processing, and release suggest alternative strategies. Cell permeant casp-1 inhibitors are a viable option, but in the light of the recent discoveries on the role of the P2X7R, we anticipate that also blockers of P2X7R may have a future as anti-inflammatory drugs.
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Footnotes |
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1 This work was supported by grants from the Italian Ministry of Education, University and Scientific Research, the Italian Association for Cancer Research, and local funds from the University of Ferrara. 
2 Address correspondence and reprint requests to Dr. Davide Ferrari, Department of Experimental and Diagnostic Medicine, Section of General Pathology, University of Ferrara, via L. Borsari 46, I-44100 Ferrara, Italy. E-mail address: dfr{at}unife.it
3 Abbreviations used in this paper: IL-1Ra, IL-1 receptor antagonist; IL-1RI, type I IL-1 receptor; casp, caspase; procasp, procaspase; ASC, apoptosis-associated speck-like protein containing a CARD; IL-1R-AcP, IL-1R accessory protein; DC, dendritic cell; SNP, single nucleotide polymorphism; P2X7R, P2X7 receptor.
Received for publication December 12, 2005. Accepted for publication January 12, 2006.
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  Q. Espinassous, E. Garcia-de-Paco, I. Garcia-Verdugo, M. Synguelakis, S. von Aulock, J.-M. Sallenave, A. N. J. McKenzie, and J. Kanellopoulos IL-33 Enhances Lipopolysaccharide-Induced Inflammatory Cytokine Production from Mouse Macrophages by Regulating Lipopolysaccharide Receptor Complex J. Immunol., July 15, 2009; 183(2): 1446 - 1455. [Abstract] [Full Text] [PDF]
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S. Tassi, S. Carta, R. Vene, L. Delfino, M. R. Ciriolo, and A. Rubartelli Pathogen-Induced Interleukin-1{beta} Processing and Secretion Is Regulated by a Biphasic Redox Response J. Immunol., July 15, 2009; 183(2): 1456 - 1462. [Abstract] [Full Text] [PDF]
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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]
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 R. Hazama, X. Qu, K. Yokoyama, C. Tanaka, E. Kinoshita, J. He, S. Takahashi, K. Tohyama, H. Yamamura, and Y. Tohyama ATP-induced osteoclast function: the formation of sealing-zone like structure and the secretion of lytic granules via microtubule-deacetylation under the control of Syk Genes Cells, July 1, 2009; 14(7): 871 - 884. [Abstract] [Full Text] [PDF]
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 S. Ceruti, G. Villa, T. Genovese, E. Mazzon, R. Longhi, P. Rosa, P. Bramanti, S. Cuzzocrea, and M. P. Abbracchio The P2Y-like receptor GPR17 as a sensor of damage and a new potential target in spinal cord injury Brain, June 15, 2009; (2009) awp147v1. [Abstract] [Full Text] [PDF]
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P. Kankkunen, J. Rintahaka, A. Aalto, M. Leino, M.-L. Majuri, H. Alenius, H. Wolff, and S. Matikainen Trichothecene Mycotoxins Activate Inflammatory Response in Human Macrophages J. Immunol., May 15, 2009; 182(10): 6418 - 6425. [Abstract] [Full Text] [PDF]
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 Y. Nakamura, N. Kambe, M. Saito, R. Nishikomori, Y.-G. Kim, M. Murakami, G. Nunez, and H. Matsue Mast cells mediate neutrophil recruitment and vascular leakage through the NLRP3 inflammasome in histamine-independent urticaria J. Exp. Med., May 11, 2009; 206(5): 1037 - 1046. [Abstract] [Full Text] [PDF]
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 M. G. Netea, C. A. Nold-Petry, M. F. Nold, L. A. B. Joosten, B. Opitz, J. H. M. van der Meer, F. L. van de Veerdonk, G. Ferwerda, B. Heinhuis, I. Devesa, et al. Differential requirement for the activation of the inflammasome for processing and release of IL-1{beta} in monocytes and macrophages Blood, March 5, 2009; 113(10): 2324 - 2335. [Abstract] [Full Text] [PDF]
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F. Scheuplein, N. Schwarz, S. Adriouch, C. Krebs, P. Bannas, B. Rissiek, M. Seman, F. Haag, and F. Koch-Nolte NAD+ and ATP Released from Injured Cells Induce P2X7-Dependent Shedding of CD62L and Externalization of Phosphatidylserine by Murine T Cells J. Immunol., March 1, 2009; 182(5): 2898 - 2908. [Abstract] [Full Text] [PDF]
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Z. Yan, S. Li, Z. Liang, M. Tomic, and S. S. Stojilkovic The P2X7 Receptor Channel Pore Dilates under Physiological Ion Conditions J. Gen. Physiol., October 27, 2008; 132(5): 563 - 573. [Abstract] [Full Text] [PDF]
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 J. Schachter, A. P. Motta, A. de Souza Zamorano, H. A. da Silva-Souza, M. Z. P. Guimaraes, and P. M. Persechini ATP-induced P2X7-associated uptake of large molecules involves distinct mechanisms for cations and anions in macrophages J. Cell Sci., October 1, 2008; 121(19): 3261 - 3270. [Abstract] [Full Text] [PDF]
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 I. Garcia-Verdugo, A. Ravasio, E. G. de Paco, M. Synguelakis, N. Ivanova, J. Kanellopoulos, and T. Haller Long-term exposure to LPS enhances the rate of stimulated exocytosis and surfactant secretion in alveolar type II cells and upregulates P2Y2 receptor expression Am J Physiol Lung Cell Mol Physiol, October 1, 2008; 295(4): L708 - L717. [Abstract] [Full Text] [PDF]
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 P. Zuo, M. Picher, S. F. Okada, E. R. Lazarowski, B. Button, R. C. Boucher, and T. C. Elston Mathematical Model of Nucleotide Regulation on Airway Epithelia: IMPLICATIONS FOR AIRWAY HOMEOSTASIS J. Biol. Chem., September 26, 2008; 283(39): 26805 - 26819. [Abstract] [Full Text] [PDF]
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K. Heiss, N. Janner, B. Mahnss, V. Schumacher, F. Koch-Nolte, F. Haag, and H.-W. Mittrucker High Sensitivity of Intestinal CD8+ T Cells to Nucleotides Indicates P2X7 as a Regulator for Intestinal T Cell Responses J. Immunol., September 15, 2008; 181(6): 3861 - 3869. [Abstract] [Full Text] [PDF]
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D. Becker, R. Woltersdorf, W. Boldt, S. Schmitz, U. Braam, G. Schmalzing, and F. Markwardt The P2X7 Carboxyl Tail Is a Regulatory Module of P2X7 Receptor Channel Activity J. Biol. Chem., September 12, 2008; 283(37): 25725 - 25734. [Abstract] [Full Text] [PDF]
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 C.-W. Chiao, R. C. Tostes, and R. C. Webb P2X7 Receptor Activation Amplifies Lipopolysaccharide-Induced Vascular Hyporeactivity via Interleukin-1{beta} Release J. Pharmacol. Exp. Ther., September 1, 2008; 326(3): 864 - 870. [Abstract] [Full Text] [PDF]
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 K. Enjyoji, K. Kotani, C. Thukral, B. Blumel, X. Sun, Y. Wu, M. Imai, D. Friedman, E. Csizmadia, W. Bleibel, et al. Deletion of Cd39/Entpd1 Results in Hepatic Insulin Resistance Diabetes, September 1, 2008; 57(9): 2311 - 2320. [Abstract] [Full Text] [PDF]
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D. Myrtek, T. Muller, V. Geyer, N. Derr, D. Ferrari, G. Zissel, T. Durk, S. Sorichter, W. Luttmann, M. Kuepper, et al. Activation of Human Alveolar Macrophages via P2 Receptors: Coupling to Intracellular Ca2+ Increases and Cytokine Secretion J. Immunol., August 1, 2008; 181(3): 2181 - 2188. [Abstract] [Full Text] [PDF]
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 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]
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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]
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 A. Piccini, S. Carta, S. Tassi, D. Lasiglie, G. Fossati, and A. Rubartelli ATP is released by monocytes stimulated with pathogen-sensing receptor ligands and induces IL-1{beta} and IL-18 secretion in an autocrine way PNAS, June 10, 2008; 105(23): 8067 - 8072. [Abstract] [Full Text] [PDF]
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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]
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N. Marina-Garcia, L. Franchi, Y.-G. Kim, D. Miller, C. McDonald, G.-J. Boons, and G. Nunez Pannexin-1-Mediated Intracellular Delivery of Muramyl Dipeptide Induces Caspase-1 Activation via Cryopyrin/NLRP3 Independently of Nod2 J. Immunol., March 15, 2008; 180(6): 4050 - 4057. [Abstract] [Full Text] [PDF]
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 F. Martinon Detection of immune danger signals by NALP3 J. Leukoc. Biol., March 1, 2008; 83(3): 507 - 511. [Abstract] [Full Text] [PDF]
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S. Adriouch, P. Bannas, N. Schwarz, R. Fliegert, A. H. Guse, M. Seman, F. Haag, and F. Koch-Nolte ADP-ribosylation at R125 gates the P2X7 ion channel by presenting a covalent ligand to its nucleotide binding site FASEB J, March 1, 2008; 22(3): 861 - 869. [Abstract] [Full Text] [PDF]
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D. Donnelly-Roberts, S. McGaraughty, C.-C. Shieh, P. Honore, and M. F. Jarvis Painful Purinergic Receptors J. Pharmacol. Exp. Ther., February 1, 2008; 324(2): 409 - 415. [Abstract] [Full Text] [PDF]
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 G. N. Schroeder and H. Hilbi Molecular Pathogenesis of Shigella spp.: Controlling Host Cell Signaling, Invasion, and Death by Type III Secretion Clin. Microbiol. Rev., January 1, 2008; 21(1): 134 - 156. [Abstract] [Full Text] [PDF]
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 X. Liu, A. Surprenant, H.-J. Mao, S. Roger, R. Xia, H. Bradley, and L.-H. Jiang Identification of Key Residues Coordinating Functional Inhibition of P2X7 Receptors by Zinc and Copper Mol. Pharmacol., January 1, 2008; 73(1): 252 - 259. [Abstract] [Full Text] [PDF]
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G. R. Dubyak Go It Alone No More P2X7 Joins the Society of Heteromeric ATP-Gated Receptor Channels Mol. Pharmacol., December 1, 2007; 72(6): 1402 - 1405. [Abstract] [Full Text] [PDF]
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L. Stokes and A. Surprenant Purinergic P2Y2 Receptors Induce Increased MCP-1/CCL2 Synthesis and Release from Rat Alveolar and Peritoneal Macrophages J. Immunol., November 1, 2007; 179(9): 6016 - 6023. [Abstract] [Full Text] [PDF]
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S. Hong, A. Brass, M. Seman, F. Haag, F. Koch-Nolte, and G. R. Dubyak Lipopolysaccharide, IFN-{gamma}, and IFN-beta Induce Expression of the Thiol-Sensitive ART2.1 Ecto-ADP-Ribosyltransferase in Murine Macrophages J. Immunol., November 1, 2007; 179(9): 6215 - 6227. [Abstract] [Full Text] [PDF]
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N. Bles, M. Horckmans, A. Lefort, F. Libert, P. Macours, H. El Housni, F. Marteau, J.-M. Boeynaems, and D. Communi Gene Expression Profiling Defines ATP as a Key Regulator of Human Dendritic Cell Functions J. Immunol., September 15, 2007; 179(6): 3550 - 3558. [Abstract] [Full Text] [PDF]
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T. Darville, L. Welter-Stahl, C. Cruz, A. A. Sater, C. W. Andrews Jr., and D. M. Ojcius Effect of the Purinergic Receptor P2X7 on Chlamydia Infection in Cervical Epithelial Cells and Vaginally Infected Mice J. Immunol., September 15, 2007; 179(6): 3707 - 3714. [Abstract] [Full Text] [PDF]
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M. W. Buczynski, D. L. Stephens, R. C. Bowers-Gentry, A. Grkovich, R. A. Deems, and E. A. Dennis TLR-4 and Sustained Calcium Agonists Synergistically Produce Eicosanoids Independent of Protein Synthesis in RAW264.7 Cells J. Biol. Chem., August 3, 2007; 282(31): 22834 - 22847. [Abstract] [Full Text] [PDF]
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F. S. Sutterwala, Y. Ogura, and R. A. Flavell The inflammasome in pathogen recognition and inflammation J. Leukoc. Biol., August 1, 2007; 82(2): 259 - 264. [Abstract] [Full Text] [PDF]
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L. Franchi, T.-D. Kanneganti, G. R. Dubyak, and G. Nunez Differential Requirement of P2X7 Receptor and Intracellular K+ for Caspase-1 Activation Induced by Intracellular and Extracellular Bacteria J. Biol. Chem., June 29, 2007; 282(26): 18810 - 18818. [Abstract] [Full Text] [PDF]
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M. Baroni, C. Pizzirani, M. Pinotti, D. Ferrari, E. Adinolfi, S. Calzavarini, P. Caruso, F. Bernardi, and F. Di Virgilio Stimulation of P2 (P2X7) receptors in human dendritic cells induces the release of tissue factor-bearing microparticles FASEB J, June 1, 2007; 21(8): 1926 - 1933. [Abstract] [Full Text] [PDF]
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 K.-H. Lee, S. S. Park, I. Kim, J. H. Kim, E. K. Ra, S.-S. Yoon, Y.-C. Hong, S. Park, and B. K. Kim P2X7 receptor polymorphism and clinical outcomes in HLA-matched sibling allogeneic hematopoietic stem cell transplantation Haematologica, May 1, 2007; 92(5): 651 - 657. [Abstract] [Full Text] [PDF]
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C. Pizzirani, D. Ferrari, P. Chiozzi, E. Adinolfi, D. Sandona, E. Savaglio, and F. Di Virgilio Stimulation of P2 receptors causes release of IL-1{beta}-loaded microvesicles from human dendritic cells Blood, May 1, 2007; 109(9): 3856 - 3864. [Abstract] [Full Text] [PDF]
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 G. Burnstock Physiology and Pathophysiology of Purinergic Neurotransmission Physiol Rev, April 1, 2007; 87(2): 659 - 797. [Abstract] [Full Text] [PDF]
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C. M. Cruz, A. Rinna, H. J. Forman, A. L. M. Ventura, P. M. Persechini, and D. M. Ojcius ATP Activates a Reactive Oxygen Species-dependent Oxidative Stress Response and Secretion of Proinflammatory Cytokines in Macrophages J. Biol. Chem., February 2, 2007; 282(5): 2871 - 2879. [Abstract] [Full Text] [PDF]
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P. Pelegrin and A. Surprenant Pannexin-1 Couples to Maitotoxin- and Nigericin-induced Interleukin-1beta Release through a Dye Uptake-independent Pathway J. Biol. Chem., January 26, 2007; 282(4): 2386 - 2394. [Abstract] [Full Text] [PDF]
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M. T. Young, P. Pelegrin, and A. Surprenant Amino Acid Residues in the P2X7 Receptor that Mediate Differential Sensitivity to ATP and BzATP Mol. Pharmacol., January 1, 2007; 71(1): 92 - 100. [Abstract] [Full Text] [PDF]
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 A. Simon and J. W. M. van der Meer Pathogenesis of familial periodic fever syndromes or hereditary autoinflammatory syndromes Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2007; 292(1): R86 - R98. [Abstract] [Full Text] [PDF]
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C. Stock, T. Schilling, A. Schwab, and C. Eder Lysophosphatidylcholine Stimulates IL-1beta Release from Microglia via a P2X7 Receptor-Independent Mechanism J. Immunol., December 15, 2006; 177(12): 8560 - 8568. [Abstract] [Full Text] [PDF]
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P. Honore, D. Donnelly-Roberts, M. T. Namovic, G. Hsieh, C. Z. Zhu, J. P. Mikusa, G. Hernandez, C. Zhong, D. M. Gauvin, P. Chandran, et al. A-740003 [N-(1-{[(Cyanoimino)(5-quinolinylamino) methyl]amino}-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide], a Novel and Selective P2X7 Receptor Antagonist, Dose-Dependently Reduces Neuropathic Pain in the Rat J. Pharmacol. Exp. Ther., December 1, 2006; 319(3): 1376 - 1385. [Abstract] [Full Text] [PDF]
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R. S. Kornbluth and G. W. Stone Immunostimulatory combinations: designing the next generation of vaccine adjuvants J. Leukoc. Biol., November 1, 2006; 80(5): 1084 - 1102. [Abstract] [Full Text] [PDF]
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 F. S. Sutterwala, Y. Ogura, D. S. Zamboni, C. R. Roy, and R. A. Flavell NALP3: a key player in caspase-1 activation Innate Immunity, August 1, 2006; 12(4): 251 - 256. [Abstract] [PDF]
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C) splice variant of the P2X7R are shown. The truncated form lacks almost the entire COOH tail (249 aa, green, red, and short black traits) but bears an extra 18 aa (light blue trait) due to inclusion of the intron between exons 10 and 11 (
