Anti-Inflammatory Preconditioning by Agonists of Adenosine A1 Receptor

Nakav, Sigal; Chaimovitz, Cidio; Sufaro, Yuval; Lewis, Eli C.; Shaked, Gad; Czeiger, David; Zlotnik, Moshe; Douvdevani, Amos

doi:10.1371/journal.pone.0002107

Cited by 61 publications

(58 citation statements)

References 31 publications

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“…We have previously shown on PMCs and peritoneal leukocytes that A 1 R is up-regulated shortly after inoculation [13,14], and we now show that A 1 R is a potent promoter of inflammation in the peritoneum. Pre-treatment with DPCPX, an A 1 R antagonist, reduced both leukocyte recruitment and the pro-inflammatory cytokine production as expected; treatment with A 1 R agonist CCPA has the reverse effects on the inflammatory cytokines.…”

Section: Discussionsupporting

confidence: 69%

“…We have previously demonstrated in a peritonitis model that adenosine levels are up-regulated following E. coli inoculation [13]. In parallel to the induction of adenosine, A 1 R levels are up-regulated together with leukocyte recruitment at the initial phase of inflammation [13,14]. The present work focuses on the events that promote the production of adenosine and the expression of A 1 R at the first phase of inflammation.…”

Section: Discussionmentioning

confidence: 91%

“…In addition, we found a sequential up-regulation of A 1 R and A 2A R on leukocytes and peritoneal mesothelial cells (PMCs). The peak of the A 1 R, the pro-inflammatory receptor, occurred in the initial phase of the inflammatory process and its activation was necessary for induction of A 2A R, the anti-inflammatory receptor of adenosine [14]. The importance of A 1 R and A 2A R in regulation of inflammation was demonstrated by the shifting of the anti-inflammatory resolution phase after pre-treatment with A 1 R agonists.…”

Section: Introductionmentioning

confidence: 98%

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Regulation of adenosine system at the onset of peritonitis

Nakav

Naamani

Chaimovitz

et al. 2009

Nephrology Dialysis Transplantation

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Background. Adenosine, a potent regulator of inflammation, is produced under stressful conditions due to degradation of ATP/ADP by the ectoenzymes CD39 and CD73. Adenosine is rapidly degraded by adenosine deaminase (ADA) or phosphorylated in the cell by adenosine kinase (AK). From four known receptors to adenosine, A 1 (A 1 R) promotes inflammation by a G i -coupled receptor. We have previously shown that A 1 R is up-regulated in the first hours following bacterial inoculation. The aim of the current study is to characterize the inflammatory mediators that regulate adenosine-metabolizing enzymes and A 1 R at the onset of peritonitis. Methods. Peritonitis was induced in CD1 mice by intraperitoneal injection of Escherichia coli. TNFα and IL-6 levels were determined in peritoneal fluid by enzymelinked immunosorbent assay. Adenosine-metabolizing enzymes and the A 1 R mRNA or protein levels were analyzed by quantitative PCR or by Western blot analysis, respectively. Results. We found that CD39 and CD73 were up-regulated in response to bacterial stimuli (6-fold the basal levels), while AK and ADA mRNA levels were down-regulated. Cytokine production and leukocyte recruitment were enhanced (2.5-fold) by treatment with an A 1 R agonist (2-chloro-N 6 -cyclopentyladenosine, 0.1mg/kg) and reduced (2.5-3-fold) by the A 1 R antagonist (8-cyclopentyl-1, 3-dipropylxanthine, 1mg/kg). In contrast to lipopolysaccharide, IL-1, TNF and IFNγ, only low IL-6 levels (0.01 ng/ml), in the presence of its soluble IL-6R (sIL-6R), were found to promote A 1 R expression on mesothelial cells. In mice, administration of neutralizing antibody to IL-6R or soluble gp130-Fc (sgp130-Fc) blocked peritoneal A 1 R up-regulation following inoculation. Conclusion. Bacterial products induce the production of adenosine by up-regulation of CD39 and CD73. Low IL-6-sIL-6R up-regulates the A 1 R to promote efficient inflammatory response against invading microorganisms.

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 98%

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Regulation of adenosine system at the onset of peritonitis

Nakav

Naamani

Chaimovitz

et al. 2009

Nephrology Dialysis Transplantation

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“…Early upregulation of A1AR suggests that A1AR initiates an antiinflammatory cascade that also involves other ARs (44).…”

Section: Discussionmentioning

confidence: 99%

Adenosine Receptor A1 Regulates Polymorphonuclear Cell Trafficking and Microvascular Permeability in Lipopolysaccharide-Induced Lung Injury

Ngamsri

Wagner

Vollmer

et al. 2010

The Journal of Immunology

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Extracellular adenosine and adenosine receptors are critically involved in various inflammatory pathways. Adenosine receptor A1 (A1AR) has been implicated in mediating transmigration of leukocytes to sites of inflammation. This study was designed to characterize the role of A1AR in a murine model of LPS-induced lung injury. LPS-induced transmigration of polymorphonuclear cells (PMNs) and microvascular permeability was elevated in A1AR−/− mice. Pretreatment of wild-type mice with the specific A1AR agonist 2′Me–2-chloro-N6-cyclopentyladenosine attenuated PMN accumulation in the interstitium and alveolar space as well as microvascular permeability. Lower PMN counts in the lungs of pretreated wild-type mice were associated with reduced amounts of the chemotactic cytokines TNF-α, IL-6, and CXCL2/3 in the bronchoalveolar lavage. Pretreatment was only effective when A1AR was expressed on hematopoietic cells as demonstrated in chimeric mice. These findings were confirmed by in vitro transmigration assays demonstrating that chemokine-induced transmigration of PMNs was reduced when PMNs but not when pulmonary endothelial or alveolar epithelial cells were pretreated. 2′Me–2-chloro-N6-cyclopentyladenosine prevented pulmonary endothelial but not epithelial cells from LPS-induced cellular remodeling and cell retraction. Our data reveal what we believe to be a previously unrecognized distinct role of A1AR for PMN trafficking and endothelial integrity in a model of acute lung injury.

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“…Importantly, mechanical stimulation of the needle via rotation every 5-minutes is thought to initially stimulate TRPv1 receptors, facilitating ATP release from sensory afferents via Pannexin-1 channels. The ATP is catabolized to ADP and eventually adenosine, stimulating P2X, P2Y and A1 receptors, respectively [92][93][94][95]. While genetically normal mice suffering from inflammation or neuropathic pain experienced significant improvements in mechanical and heat analgesia secondary to DN, A1 receptor knock-out mice did not [92].…”

Section: The Effect Of Dry Needling Mechanotransduction On P1 Purinermentioning

confidence: 99%

Peripheral and Spinal Mechanisms of Pain and Dry Needling Mediated Analgesia: A Clinical Resource Guide for Health Care Professionals

Butts¹,

Dunning²

2016

Int J Phys Med Rehabil

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There are a number of biochemical, biomechanical, endocrinological and neurovascular mechanisms underpinning the anti-nociceptive and anti-inflammatory effects of dry needling (DN). While myofascial trigger points likely play a role in peripheral pain, a diagnostic tool for localizing them has not been validated, and DN studies that have targeted trigger points to elicit localized twitch responses have reported mixed results. Therefore, the mechanism responsible for DN-mediated analgesia may be more complicated. DN activates opioid-based pain reduction, mediated by endogenous cannabinoids and the sympathetic nervous system, and non-opioid pain relief via serotonin and norepinephrine from the brain stem. DN also triggers the hypothalamic-pituitary-adrenal axis centrally and the corticotropin releasing hormone-proopiomelanocortin-corticosteroid axis locally to inhibit cox-2, reducing inflammatory cytokines. Recent studies demonstrate that DN combined with mechanical and/or electrical stimulation may reverse PKC-mediated peripheral hyperalgesic priming by normalizing nociceptive channels, to include TRPV, ASIC, TTX and P2X/Y. Electrical DN (EDN) stimulates immune cells, fibroblasts and keratinocytes to release CGRP and substance-P, altering the stimulation of TTX receptors to reverse hyperalgesia. It also encourages the supraoptic nucleus to release oxytocin to quiet ASIC receptors peripherally and stimulate opioid interneurons spinally. Moreover, EDN inhibits ERK1/2 kinase pathways of inflammation in the spinal cord and stimulates Aδ fibers and N/OFQ to reverse C-fiber mediated central changes. Mechanotransduction of fibroblasts and peripheral nerves via TRPV1 and P2X/Y-mediated intracellular Ca 2+ wave propagation and subsequent activation of the nucleus accumbens inhibits spinal pain transmission via glycinergic and opioidergic interneurons. The increased ATP is metabolized to adenosine, which activates P1 purinergic receptors, events considered key to DN analgesia and rho kinase-based tissue remodeling. Mechanotransduction-mediated release of histamine further explains analgesia secondary to needling points distal to pain. DN-mediated analgesia is dependent on a number of synergistic physiologic events involving biochemical and mechanical processes in neural, connective and muscle tissue.

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Anti-Inflammatory Preconditioning by Agonists of Adenosine A1 Receptor

Cited by 61 publications

References 31 publications

Regulation of adenosine system at the onset of peritonitis

Regulation of adenosine system at the onset of peritonitis

Adenosine Receptor A1 Regulates Polymorphonuclear Cell Trafficking and Microvascular Permeability in Lipopolysaccharide-Induced Lung Injury

Peripheral and Spinal Mechanisms of Pain and Dry Needling Mediated Analgesia: A Clinical Resource Guide for Health Care Professionals

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