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INFLAMMATION AND IMMUNOPHARMACOLOGY

Activation of the Adenosine A₃ Receptor in RAW 264.7 Cells Inhibits Lipopolysaccharide-Stimulated Tumor Necrosis Factor- Release by Reducing Calcium-Dependent Activation of Nuclear Factor-B and Extracellular Signal-Regulated Kinase 1/2

Departments of Pharmacology (L.M., S.C.P., D.M.H., L.P.R., V.R.) and Surgery (L.P.R.), Southern Illinois University School of Medicine, Springfield, Illinois

Bacterial lipopolysaccharide (LPS) activates the immune system and promotes inflammation via Toll-like receptor (TLR) 4, which regulates the synthesis and release of tumor necrosis factor (TNF)- and other inflammatory cytokines. Previous studies have shown that the nucleoside adenosine suppresses LPS-stimulated TNF- release in human UB939 macrophages by activating an adenosine A₃ receptor (A₃AR) subtype on these cells. In this study, we examined the mechanism(s) underlying A₃AR-dependent inhibition of TNF- release in a mouse (RAW 264.7) cell line. Treatment of RAW 264.7 cells with LPS (3 µg/ml) increased TNF- release, which was reduced in a dose-dependent manner by adenosine analogs N⁶-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (IB-MECA) and R-phenylisopropyladenosine and reversed by selective A₃AR blockade. The increase in TNF- release was preceded by an increase in intracellular Ca²⁺ levels. Inhibition of intracellular Ca²⁺ release by IB-MECA, a selective agonist of the A₃AR, or with BAPTA-AM, an intracellular Ca²⁺ chelator, reduced LPS-stimulated TNF- release. Activation of the A₃AR or inhibition of intracellular Ca²⁺ release also reduced LPS-stimulated nuclear factor-B (NF-B) activation and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. Similar inhibition by A₃AR was observed for LPS-stimulated inducible nitric-oxide synthase. These data support the contention that inhibition of LPS-stimulated release of inflammatory molecules, such as TNF- and NO via the A₃AR, involves suppression of intracellular Ca²⁺signaling, leading to suppression of NF-B and ERK1/2 pathways.

Address correspondence to: Dr. Vickram Ramkumar, Dept. of Pharmacology, Southern Illinois University School of Medicine, P.O. Box 19230, Springfield, IL 62794-1222. E-mail: vramkumar{at}siumed.edu

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