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Adenosine downregulates cytokine‐induced expression of intercellular adhesion molecule‐1 on rheumatoid synovial fibroblasts independently of adenosine receptor signaling
Author(s) -
Nakazawa Takashi,
Koshiba Masahiro,
Kosaka Hidekazu,
Tsuji Goh,
Nakamachi Yuji,
Saura Ryuichi,
Kurosaka Masahiro,
Tanaka Yoshiya,
Kumagai Shunichi
Publication year - 2003
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.10186
Subject(s) - adenosine a3 receptor , adenosine , adenosine a2b receptor , adenosine receptor , purinergic signalling , adenosine a1 receptor , chemistry , adenosine deaminase inhibitor , cytokine , agonist , adenosine deaminase , medicine , microbiology and biotechnology , endocrinology , biology , receptor , biochemistry , immunology
Adhesion of fibroblast‐like synoviocytes (FLSs) to T cells through the interaction of lymphocyte function‐associated antigen‐1 (LFA‐1) and intercellular adhesion molecule‐1 (ICAM‐1) plays a pivotal role in the pathogenesis of rheumatoid arthritis (RA). We therefore used flow cytometry and quantitative polymerase chain reaction (PCR) to examine the effect of adenosine and its derivatives on expression of ICAM‐1 induced by tumor necrosis factor‐alpha and interferon‐gamma in primary rheumatoid FLSs (RA‐FLSs) and E11 cells, an RA‐FLS line. Exposing cells to adenosine (5–500 µM) for 24 h in the presence of coformycin, an adenosine deaminase inhibitor, concentration‐dependently inhibited cytokine‐induced transcription of ICAM‐1 mRNA, as well as subsequent surface expression of the protein. Although transcription of all four adenosine receptor isoforms has been detected in FLSs, neither the A 1 receptor agonist R‐PIA, the A 2A receptor agonist CGS21680 nor the A 3 agonist Cl‐IB‐MECA had any effect on cytokine‐induced ICAM‐1 expression. Conversely, A 1 /A 2 receptor antagonist xanthine amine congener and A 2A antagonist ZM240385 both failed to suppress the effect of adenosine. Adenosine appears to inhibit cytokine‐induced ICAM‐1 expression in FLSs independently of adenosine receptor‐mediated signaling. By contrast, the effect of adenosine was neutralized by nitrobenzylmercaptopurin, a nucleoside transporter inhibitor, or by ABT702, an adenosine kinase inhibitor. This suggests that adenosine taken up via the nucleoside transporter is phosphorylated by adenosine kinase, and the resultant phospho‐adenosine interferes with the ICAM‐1 transcription and cell surface expression. Downregulation of T cell–FLS interaction by adenosine may thus represent a novel approach to the treatment of RA. Drug Dev. Res. 58:368–376, 2003. © 2003 Wiley‐Liss, Inc.