Inhibition by adenosine of reactive oxygen metabolite production by human polymorphonuclear leucocytes

Roberts, Peter A.; Newby, AC; Hallett, Maurice Bartlett; Campbell, Anthony K.

doi:10.1042/bj2270669

Cited by 106 publications

(33 citation statements)

References 13 publications

(12 reference statements)

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“…It has been demonstrated (12,14,(25)(26)(27)(28)(29)(30) that adenosine occupies specific A2 receptors on the surface of neutrophils to inhibit the generation of toxic oxygen metabolites such as 0°-, H202, and adherence to endothelium. Thus, for example, increased release of adenosine from synovial cells could dampen both the acute and chronic inflammation present in the joints of patients with rheumatoid arthritis.…”

Section: Discussionmentioning

confidence: 99%

Methotrexate inhibits neutrophil function by stimulating adenosine release from connective tissue cells.

Cronstein

Eberle

Gruber

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

314

158

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(IC50, 9 nM) and stimulated neutrophils (IC5*, 13 nM). Methotrexate treatment inhibited neutrophil adherence by enhing adenosine release from fibroblasts since digestion of extracellular adenosine by added adenosine deaminase completely abrogated the effect ofmethotrexate on neutrophil adherence without, itself, affecting adherence. One hypothesis that explains the effect of methotrexate on adenosine release is that, by inhibiton of 5-aminoimidazole-

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Section: Discussionmentioning

confidence: 99%

Methotrexate inhibits neutrophil function by stimulating adenosine release from connective tissue cells.

Cronstein

Eberle

Gruber

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

314

158

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“…Stimulation of the adenosine receptors selectively found on PMNs (A 2 receptors) results in inhibition of superoxide anion release following FMLP stimulation [19,20]. Therefore, if stimulation of the A 2 receptor results in inhibition of PMN function, then competitive antagonism of the receptor would, potentially, have the opposite (stimulatory) effect.…”

Section: Discussionmentioning

confidence: 99%

The effects of beta 2-agonists and methylxanthines on neutrophil function in vitro

Llewellyn-Jones

Stockley²

1994

Eur Respir J

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We have assessed the effects of the β 2 -agonist, terbutaline, and the methylxanthine, aminophylline, on PMN functions in vitro at both therapeutic and higher concentrations.At therapeutic levels, both agents increased PMN chemotaxis to formyl-methionylleucyl-phenylalanine (FMLP) in a dose-dependent manner from a control value of 22.5±3.58 cells·field -1 to 26.1±4.73 cells·field -1 with 4 mg·l -1 terbutaline, and to 26.3±4.49 cells·field -1 with 20 mg·l -1 aminophylline. When the cells were preincubated with higher doses of the agents in separate experiments there was inhibition of chemotaxis from a control value of 31.1±2.06 cells·field -1 to 18.3±0.82 cells·field -1 at 160 mg·l -1 terbutaline, and to 16.1±0.77 cells·field -1 at 400 mg·l -1 aminophylline. A similar effect was seen when the PMNs were preincubated with terbutaline and aminophylline prior to assessment of superoxide anion generation, with stimulation of superoxide release at therapeutic levels of the drugs and inhibition at higher doses (19% increase from resting control cells at terbutaline 4 mg·l -1 and 53% reduction at 160 mg·l -1 ; 28% increase with aminophylline 20 mg·l -1 and 22% reduction at 400 mg·l -1 ). Both terbutaline and aminophylline had no effect on PMN degranulation, as assessed by the degradation of fibronectin.These data suggest that terbutaline and aminophylline exert a biphasic effect on PMN functions in vitro, and may have detrimental effects on lung tissues at therapeutic levels through potentiation of PMN recruitment and activation. However, the observed effects of therapeutic doses of these agents on in vitro PMN functions were relatively small and, therefore, the clinical relevance of these results is, as yet, uncertain.

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“…We and others have previously reported that adenosine and its analogues inhibit O2 generation by occupying specific adenosine A2 receptors on the neutrophil (2, 3,5,6). More recently we have reported that adenosine occupies a similar receptor to promote chemotaxis (2,4).…”

Section: Introductionmentioning

confidence: 98%

The adenosine/neutrophil paradox resolved: human neutrophils possess both A1 and A2 receptors that promote chemotaxis and inhibit O2 generation, respectively.

Cronstein

Daguma²,

Nichols³

et al. 1990

J. Clin. Invest.

362

217

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Occupancy of specific receptors on neutrophils by adenosine or its analogues diminishes the stimulated release of toxic oxygen metabolites from neutrophils, while paradoxically promoting chemotaxis. We now report evidence that two distinct adenosine receptors are found on neutrophils (presumably the Al and A2 receptors of other cell types). These adenosine receptors modulate chemotaxis and 02 generation, respectively. N6-Cyclopentyladenosine (CPA), a selective A, agonist, promoted neutrophil chemotaxis to the chemoattractant FMLP as well as or better than 5'N-ethylcarboxamidoadenosine (NECA). In contrast, CPA did not inhibit O2 generation stimulated by FMLP. Pertussis toxin completely abolished promotion of chemotaxis by CPA but enhanced inhibition by NECA of 02 generation. Disruption of microtubules by colchicine or vinblastine also abrogated the enhancement by NECA of chemotaxis whereas these agents did not markedly interfere with inhibition by NECA of°2 generation. FMLP receptors, once they have bound ligand, shift to a high affinity state and become associated with the cytoskeleton. NECA significantly increased association of I3HIFMLP with cytoskeletal preparations as it inhibited 2.-Disruption of microtubules did not prevent NECA from increasing association of PHIFMLP with cytoskeletal preparations. Additionally, CPA (Al agonist) did not increase binding of IHIFMLP to the cytoskeleton as well as NECA (A2 agonist). These studies indicate that occupancy of one class of adenosine receptors (Al) promotes chemotaxis by a mechanism requiring intact microtubules and G proteins whereas engagement of a second class of receptors (A2) inhibits 0-generation. Signalling via A2 receptors is independent of microtubules, insensitive to pertussis toxin and is associated with binding of [HjFMLP to cytoskeletal preparations.

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Inhibition by adenosine of reactive oxygen metabolite production by human polymorphonuclear leucocytes

Cited by 106 publications

References 13 publications

Methotrexate inhibits neutrophil function by stimulating adenosine release from connective tissue cells.

Methotrexate inhibits neutrophil function by stimulating adenosine release from connective tissue cells.

The effects of beta 2-agonists and methylxanthines on neutrophil function in vitro

The adenosine/neutrophil paradox resolved: human neutrophils possess both A1 and A2 receptors that promote chemotaxis and inhibit O2 generation, respectively.

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