Journal article
Activation of the A3 adenosine receptor inhibits fMLP-induced Rac activation in mouse bone marrow neutrophils
Biochemical pharmacology, Vol.79(11), pp.1667-1673
06/01/2010
DOI: 10.1016/j.bcp.2010.02.002
PMCID: PMC2847012
PMID: 20149782
Abstract
Adenosine is released from injured or hypoxic tissues where it exerts numerous anti-inflammatory effects including suppression of neutrophil functions. Although most previous work has implicated the A2AAR, we have recently shown that selective activation of the abundantly expressed A3AR inhibits neutrophil superoxide production and chemotaxis providing a potential mechanistic explanation for the efficacy of A3AR agonists in experimental animal models of inflammation. In this study, we hypothesized that the A3AR suppresses neutrophil functions by inhibiting the monomeric GTPase Rac, a central regulator of chemokine-directed neutrophil migration and superoxide production. We found that pre-treating neutrophils with the highly selective A3AR agonist CP-532,903 reduced fMLP-induced Rac activation using an ELISA-based assay that detects all three Rac isoforms. CP-532,903 also inhibited fMLP-induced F-actin formation, a downstream effector function of Rac relevant to neutrophil migration, but not activation of ERK1/2 or p38. Pre-treating neutrophils with CP-532,903 did not stimulate cAMP production or alter fMLP-induced calcium transients, implicating that A3AR stimulation does not inhibit Rac activation or neutrophil activities by suppressing Ca2+ signaling, elevating the intracellular concentration of cAMP, or by cross-desensitizing fMLP receptors. Our results suggest that activation of the A3AR signals to suppress neutrophil functions by interfering with the monomeric GTPase Rac, thus contributing to the ant-inflammatory actions of adenosine.
Details
- Title: Subtitle
- Activation of the A3 adenosine receptor inhibits fMLP-induced Rac activation in mouse bone marrow neutrophils
- Creators
- Dharini VAN DER HOEVEN - Medical College of WisconsinElizabeth T Gizewski - Medical College of WisconsinJohn A Auchampach - Medical College of Wisconsin
- Resource Type
- Journal article
- Publication Details
- Biochemical pharmacology, Vol.79(11), pp.1667-1673
- DOI
- 10.1016/j.bcp.2010.02.002
- PMID
- 20149782
- PMCID
- PMC2847012
- NLM abbreviation
- Biochem Pharmacol
- ISSN
- 0006-2952
- eISSN
- 1873-2968
- Publisher
- Elsevier
- Number of pages
- 7
- Language
- English
- Date published
- 06/01/2010
- Academic Unit
- Oral Pathology, Radiology and Medicine; Dentistry Administration
- Record Identifier
- 9985157545002771
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