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Open Access 01-02-2006 | Research article

The PI3K–NF-κB signal transduction pathway is involved in mediating the anti-inflammatory effect of IB-MECA in adjuvant-induced arthritis

Authors: Pnina Fishman, Sara Bar-Yehuda, Lea Madi, Lea Rath-Wolfson, Avivit Ochaion, Shira Cohen, Ehud Baharav

Published in: Arthritis Research & Therapy | Issue 1/2006

Abstract

The anti-inflammatory effect of adenosine was previously found to be mediated via activation of the A₃ adenosine receptor (A₃AR). The aim of the present study was to decipher the molecular mechanism involved with the inhibitory effect of IB-MECA, an A₃AR agonist, on adjuvant-induced arthritis.

The adjuvant-induced arthritis rats responded to IB-MECA treatment with a decrease in the clinical score and the pathological score of the disease. The response to IB-MECA was neutralized by the antagonist MRS 1220, confirming that the efficacy of the synthetic agonist was A₃AR mediated.

The A₃AR protein expression level was highly expressed in the synovia, in the peripheral blood mononuclear cells and in the drain lymph node (DLN) tissues of adjuvant-induced arthritis rats in comparison with naïve animals. Downregulation of A₃AR expression was noted upon treatment with IB-MECA. Analysis of synovia and DLN protein extracts revealed a decreased expression level of PI3K, PKB/Akt, IKK, NF-κB and tumor necrosis factor alpha, known to affect survival and apoptosis of inflammatory cells, whereas the caspase-3 level was upregulated.

Taken together, high A₃AR expression is found in the synovia, in the immune cells in the DLN and in peripheral blood mononuclear cells. IB-MECA, an orally bioavailable molecule, activates the A₃AR, inducing receptor downregulation and the initiation of a molecular mechanism that involves de-regulation of the PI3K–NF-κB signaling pathway. As a result, a potent anti-inflammatory effect manifested in the improvement of the disease clinical score and pathological score occurs. The finding that the A₃AR expression level in the peripheral blood mononuclear cells and in the DLN reflects the receptor status in the remote inflammatory site suggests use of the A₃AR as a follow-up biomarker.

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Title: The PI3K–NF-κB signal transduction pathway is involved in mediating the anti-inflammatory effect of IB-MECA in adjuvant-induced arthritis
Authors: Pnina Fishman
Sara Bar-Yehuda
Lea Madi
Lea Rath-Wolfson
Avivit Ochaion
Shira Cohen
Ehud Baharav
Publication date: 01-02-2006
Publisher: BioMed Central
Published in: Arthritis Research & Therapy / Issue 1/2006
Electronic ISSN: 1478-6362
DOI: https://doi.org/10.1186/ar1887

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