Lipopolysaccharide Inhibits the Channel Activity of the P2X7 Receptor

Leiva-Salcedo, Elías; Coddou, Claudio; Rodríguez, Felipe; Penna, Ana Lúcia Barretto; López, Ximena; Neira, Tanya; Fernández, Ricardo; Imarai, Mónica; Rı́os, Miguel A.; Escobar, Jorge; Montoya, Margarita; Huidobro‐Toro, J. Pablo; Escobar, Alejandro; Acuña-Castillo, Claudio

doi:10.1155/2011/152625

Cited by 9 publications

(9 citation statements)

References 58 publications

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“…A recent report suggested that LPS does not induce P2X7R-related activity in P2X7R expressing HEK293 cells (Leiva-Salcedo et al, 2011). Therefore, we tested whether LPS directly binds to P2X7R.…”

Section: Resultsmentioning

confidence: 99%

“…This was associated with less necrotic cell death and reduced pro-IL-1α secretion into the BALF. However, LPS alone is unable to induce any P2X7R-related activity, suggesting that the P2X7R is not directly activated by endotoxin in vitro (Leiva-Salcedo et al, 2011). In our in vitro experiments, we also detected only weak fluorescence for LPS-Alexa594 in P2X7R-expressing HEK293 cells and we did not see any Ca 2+ mobilization in response to LPS in those cells.…”

Section: Discussionmentioning

confidence: 99%

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Lipopolysaccharide Induces Alveolar Macrophage Necrosis via CD14 and the P2X7 Receptor Leading to Interleukin-1α Release

et al. 2015

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SUMMARY Acute lung injury (ALI) remains a serious health issue with little improvement in our understanding of the pathophysiology and therapeutic approaches. We investigated the mechanism that lipopolysaccharide (LPS) induces early neutrophil recruitment to lungs and increases pulmonary vascular permeability during ALI. Intratracheal LPS induced release of pro-interleukin-1α (IL-1α) from necrotic alveolar macrophages (AM), which activated endothelial cells (EC) to induce vascular leakage via loss of vascular endothelial (VE)-cadherin. LPS triggered the AM purinergic receptor P2X7(R) to induce Ca2+ influx and ATP depletion, which led to necrosis. P2X7R deficiency significantly reduced necrotic death of AM and release of pro-IL-1α into the lung. CD14 was required for LPS binding to P2X7R, as CD14 neutralization significantly diminished LPS induced necrotic death of AM and pro-IL-1α release. These results demonstrate a key role for pro-IL-1α from necrotic alveolar macrophages in LPS-mediated ALI, as a critical initiator of increased vascular permeability and early neutrophil infiltration.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide Induces Alveolar Macrophage Necrosis via CD14 and the P2X7 Receptor Leading to Interleukin-1α Release

et al. 2015

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“…Afterward, mice were sacrificed by cervical dislocation, and the spleen and the tumor were removed. Spleen was disaggregated using a stainless-steel mesh (100 µm), erythrocytes were removed by differential lysis using an ACK buffer (NH 4 Cl 155 mM, KHCO 3 10 mM, Na 2 EDTA 1 mM, pH 7.3) with gentle agitation for 5 min (Leiva-Salcedo et al, 2011), then centrifuged at 1200 g for 10 min and discarded the supernatant. In C57BL/6 wild-type mice, splenocytes were suspended at 2 × 10 6 cells/ml in 1 ml of cold blocking buffer (2% FBS in PBS, IF buffer) and incubated at 4°C per 30 min.…”

Section: Methodsmentioning

confidence: 99%

Lithraea caustic (Litre) Extract Promotes an Antitumor Response Against B16 Melanoma

et al. 2019

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Melanoma immunotherapy, specifically the autotransplant of dendritic cells charged with tumors antigens, has shown promising results in clinical trials. The positive clinical effects of this therapy have been associated to increased Th17 response and delayed-type hypersensitivity (DTH) against to tumor antigens. Some synthetic compounds, such as diphenylcyclopropenone (DPCP), are capable of triggering a DTH response in cutaneous malignancies and also to induce clinically relevant effects against melanoma. In this work, we evaluated Litre extract (LExT), a standardized extract of a Chilean stinging plant, Lithraea caustic (Litre). As Litre plant is known to induce DTH, we used a murine B16 melanoma model to compare the topical and intratumor efficacy of LExT with synthetic DTH inducers (DPCP and 2,4-dinitrochlorobenzene [DNCB]). LExt contained mainly long chain catechols and sesquiterpenes. The intratumor injection of LExT induced a significant delay in tumor growth, similarly topical treatment of an established tumor with 0.1% LExT ointment induced a growth delay and even tumor regression in 15% of treated animals. No significant changes were observed on the T-cell populations associated to LExT treatment, and neither DNCB nor DPCP were capable to induce none of the LExT-induced antitumoral effects. Interestingly, our results indicate that LExT induces an antitumor response against melanoma in a mouse model and could bring a new –and affordable- treatment for melanoma in humans.

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“…They found that LPS alone was unable to induce any P2X7 receptor-related activity, suggesting that the receptor is not directly activated by the endotoxin. On the other hand, pre-application of LPS inhibited P2X7 receptor ionic channel and pore function in HEK293 cells [ 70 ]. Compellingly, another bacterial product lipooligosacharide also is able to promote the release of ATP and its derivatives, which can enhance the processes of cell activation and apoptosis.…”

Section: Natural Products From Microorganisms Acting On P2 Receptomentioning

confidence: 99%

Action of Natural Products on P2 Receptors: A Reinvented Era for Drug Discovery

et al. 2012

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Natural products contribute significantly to available drug therapies and have been a rich source for scientific investigation. In general, due to their low cost and traditional use in some cultures, they are an object of growing interest as alternatives to synthetic drugs. With several diseases such as cancer, and inflammatory and neuropathic diseases having been linked to the participation of purinergic (P2) receptors, there has been a flurry of investigations on ligands within natural products. Thirty-four different sources of these compounds have been found so far, that have shown either agonistic or antagonistic effects on P2 receptors. Of those, nine different plant sources demonstrated effects on P2X2, P2X3, P2X7, and possibly P2Y12 receptor subtypes. Microorganisms, which represent the largest group, with 26 different sources, showed effects on both receptor subtypes, ranging from P2X1 to P2X4 and P2X7, and P2Y1, P2Y2, P2Y4, and P2Y6. In addition, there were seventeen animal sources that affected P2X7 and P2Y1 and P2Y12 receptors. Natural products have provided some fascinating new mechanisms and sources to better understand the P2 receptor antagonism. Moreover, current investigations should clarify further pharmacological mechanisms in order to consider these products as potential new medicines.

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Lipopolysaccharide Inhibits the Channel Activity of the P2X7 Receptor

Cited by 9 publications

References 58 publications

Lipopolysaccharide Induces Alveolar Macrophage Necrosis via CD14 and the P2X7 Receptor Leading to Interleukin-1α Release

Lipopolysaccharide Induces Alveolar Macrophage Necrosis via CD14 and the P2X7 Receptor Leading to Interleukin-1α Release

Lithraea caustic (Litre) Extract Promotes an Antitumor Response Against B16 Melanoma

Action of Natural Products on P2 Receptors: A Reinvented Era for Drug Discovery

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