Adenosine A2A receptor signaling attenuates LPS-induced pro-inflammatory cytokine formation of mouse macrophages by inducing the expression of DUSP1.
Adenosine is known to reduce inflammation by suppressing the activity of most immune cells. Previous studies have shown that lipopolysaccharide (LPS) stimulated mouse macrophages produce adenosine, and the adenosine A2A receptor (A2AR) signaling activated in an autocrine manner attenuates LPS-induced pro-inflammatory cytokine formation. It has been suggested that A2AR signaling inhibits LPS-induced pro-inflammatory cytokine production through a unique cAMP-dependent, but PKA- and Epac-independent signaling pathway. However, the mechanism of inhibition was not identified so far. Here we report that LPS stimulation enhances A2AR expression in mouse bone marrow derived macrophages, and loss of A2ARs results in enhanced LPS-induced pro-inflammatory response. Loss of A2ARs in A2AR null macrophages did not alter the LPS-induced NF-κB activation, but an enhanced basal and LPS-induced phosphorylation of MAP kinases (especially that of JNKs) was detected in A2AR null cells. A2AR signaling did not alter the LPS-induced phosphorylation of their upstream kinases, but by regulating adenylate cyclase activity it enhanced the expression of dual specific phosphatase (DUSP)1, a negative regulator of MAP kinases. As a result, lower basal and LPS-induced DUSP1 mRNA and protein levels can be detected in A2AR null macrophages. Silencing of DUSP1 mRNA expression resulted in higher basal and LPS-induced JNK phosphorylation and LPS-induced pro-inflammatory cytokine formation in wild type macrophages, but had no effect on that in A2AR null cells. Our data indicate that A2AR signaling regulates both basal and LPS-induced DUSP1 levels in macrophages via activating the adenylate cyclase pathway.
['Köröskényi|Krisztina|K|', 'Kiss|Beáta|B|', 'Szondy|Zsuzsa|Z|']
D058908:Adenosine A2 Receptor Agonists D000262:Adenylyl Cyclases D000818:Animals D002478:Cells, Cultured D016207:Cytokines D054638:Dual Specificity Phosphatase 1 D005838:Genotype D018836:Inflammation Mediators D048031:JNK Mitogen-Activated Protein Kinases D008070:Lipopolysaccharides D008264:Macrophages D018345:Mice, Knockout D052002:NF-kappa B p50 Subunit D010641:Phenotype D010766:Phosphorylation D034622:RNA Interference D043705:Receptor, Adenosine A2A D015398:Signal Transduction D013997:Time Factors D051996:Transcription Factor RelA D014162:Transfection
Adenosine A2A receptor Macrophages Lipopolysaccharide Dual specific phosphatase-1 cAMP