Journal
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Volume 316, Issue 1, Pages 71-78Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/jpet.105.091868
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Funding
- NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS [R01DC002396] Funding Source: NIH RePORTER
- NIDCD NIH HHS [R01 DC 02396] Funding Source: Medline
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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)-alpha and other inflammatory cytokines. Previous studies have shown that the nucleoside adenosine suppresses LPS-stimulated TNF-alpha release in human UB939 macrophages by activating an adenosine A(3) receptor ( A(3)AR) subtype on these cells. In this study, we examined the mechanism( s) underlying A(3)AR-dependent inhibition of TNF-alpha release in a mouse ( RAW 264.7) cell line. Treatment of RAW 264.7 cells with LPS ( 3 mu g/ ml) increased TNF-alpha 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 A(3)AR blockade. The increase in TNF-alpha release was preceded by an increase in intracellular Ca2+ levels. Inhibition of intracellular Ca2+ release by IB-MECA, a selective agonist of the A(3)AR, or with BAPTA-AM, an intracellular Ca2+ chelator, reduced LPS-stimulated TNF-alpha release. Activation of the A(3)AR or inhibition of intracellular Ca2+ release also reduced LPS-stimulated nuclear factor-kappa B ( NF-kappa B) activation and extracellular signal-regulated kinase 1/2 ( ERK1/2) phosphorylation. Similar inhibition by A(3)AR 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-alpha and NO via the A(3)AR, involves suppression of intracellular Ca2+ signaling, leading to suppression of NF-kappa B and ERK1/2 pathways.
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