P2 Purinoceptors in the Immune System

Virgilio, Francesco Di; Ferrari, Davide; Falzoni, Simonetta; Chiozzi, Paola; Munerati, M.; Steinberg, Thomas H.; Baricordi, O. R.

doi:10.1002/9780470514900.ch17

Cited by 30 publications

(17 citation statements)

References 41 publications

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“…8D, a reduction of pannexin-1 expression of at least 70% caused no decrease in EB uptake, indicating that pannexin-1 was likely not implicated in this process. In comparison, in macrophages this same siRNA reduced pannexin-1 expression to approximately the same level, and in parallel dye uptake was decreased by 70 -80% (51).…”

Section: Discussionmentioning

confidence: 81%

The Human Cathelicidin LL-37 Modulates the Activities of the P2X7 Receptor in a Structure-dependent Manner

Tomasinsig

Pizzirani

Skerlavaj

et al. 2008

Journal of Biological Chemistry

132

117

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Extracellular ATP, released at sites of inflammation or tissue damage, activates the P2X 7 receptor, which in turn triggers a range of responses also including cell proliferation. In this study the ability of the human cathelicidin LL-37 to stimulate fibroblast growth was inhibited by commonly used P2X 7 blockers. We investigated the structural requirements of the growth-promoting activity of LL-37 and found that it did not depend on helix sense (the all-D analog was active) but did require a strong helix-forming propensity in aqueous solution (a scrambled analog and primate LL-37 orthologs devoid of this property were inactive). The involvement of P2X 7 was analyzed using P2X 7 -expressing HEK293 cells. LL-37 induced proliferation of these cells, triggered Ca 2؉ influx, promoted ethidium bromide uptake, and synergized with benzoyl ATP to enhance the pore and channel functions of P2X 7 . The activity of LL-37 had an absolute requirement for P2X 7 expression as it was blocked by the P2X 7 inhibitor KN-62, was absent in cells lacking P2X 7 , and was restored by P2X 7 transfection. Of particular interest, LL-37 led to pore-forming activity in cells expressing a truncated P2X 7 receptor unable to generate the non-selective pore typical of the full-length receptor. Our results indicate that P2X 7 is involved in the proliferative cell response to LL-37 and that the structural/aggregational properties of LL-37 determine its capacity to modulate the activation state of P2X 7 .

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Section: Discussionmentioning

confidence: 81%

The Human Cathelicidin LL-37 Modulates the Activities of the P2X7 Receptor in a Structure-dependent Manner

Tomasinsig

Pizzirani

Skerlavaj

et al. 2008

Journal of Biological Chemistry

132

117

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“…Its remarkable efficiency and plasticity as an alarm signal strongly depends on the diverse of ATP-selective plasma membrane receptors expressed by immune cells. Very interestingly, even before all ATP receptors (P2 receptors) expressed by immune cells were cloned and fully characterized, it was clear that stimulation with extracellular ATP was able to cause a dramatic acceleration of pro-IL-1β processing and release from monocytes/macrophages, as well as from microglial cells, and this was very likely a receptor-mediated event (Perregaux and Gabel, 1994; Di Virgilio et al, 1996; Ferrari et al, 1996). About at the same time the P2X7R was cloned (Surprenant et al, 1996), and soon after identified as the molecule responsible for ATP-dependent mature IL-1β release (Ferrari et al, 1997).…”

Section: Resultsmentioning

confidence: 99%

The P2X7 Receptor-Interleukin-1 Liaison

et al. 2017

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Interleukin-1β (IL-1β) plays a central role in stimulation of innate immune system and inflammation and in several chronic inflammatory diseases. These include rare hereditary conditions, e.g., auto-inflammatory syndromes, as well as common pathologies, such as type II diabetes, gout and atherosclerosis. A better understanding of IL-1β synthesis and release is particularly relevant for the design of novel anti-inflammatory drugs. One of the molecules mainly involved in IL-1β maturation is the P2X7 receptor (P2X7R), an ATP-gated ion channel that chiefly acts through the recruitment of the NLRP3 inflammasome-caspase-1 complex. In this review, we will summarize evidence supporting the key role of the P2X7R in IL-1β production, with special emphasis on the mechanism of release, a process that is still a matter of controversy. Four different models have been proposed: (i) exocytosis via secretory lysosomes, (ii) microvesicles shedding from plasma membrane, (iii) release of exosomes, and (iv) passive efflux across a leaky plasma membrane during pyroptotic cell death. All these models involve the P2X7R.

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“…Two years after, again Gabel and his coworkers showed that extracellular ATP was an extremely potent stimulus for IL-1b processing and release and that K + efflux was the trigger (Perregaux and Gabel, 1994). With the identification and cloning of P2X7R, the plasma membrane pathway responsible for the large ATP-stimulated outward K + fluxes became obvious (Di Virgilio et al, 1996;Surprenant et al, 1996). The P2X7R was soon identified as the sole P2 receptor coupled to IL-1b and IL-18 processing and release (Ferrari et al, 1997;Perregaux et al, 2000;Sanz and Di Virgilio, 2000;Mehta et al, 2001) and in fact as one of the most potent inducers of the maturation and release of these cytokines.…”

Section: Mechanism Of Activation Of the Inflammasomementioning

confidence: 99%