Abstract
The alternatively activated macrophage phenotype induced by IL-10 is called M2c. Adenosine is an endogenous purine nucleoside that accumulates in the extracellular space in response to metabolic disturbances, hypoxia, inflammation, physical damage, or apoptosis. As adenosine is known to regulate classically activated M1 and IL4- and IL-13-activated M2a macrophages, the goal of the present study was to explore its effects on M2c macrophages. We found that adenosine augmented the IL-10-induced expression of TIMP-1 and arginase-1 by the mouse macrophage cell line RAW 264.7 and by mouse BMDMs. The effects of AR stimulation on IL-10-induced TIMP-1 or arginase-1 expression were lacking in A2BAR KO macrophages. The role of A2BAR on TIMP-1 production of RAW 264.7 cells was confirmed with specific agonist BAY606583 and antagonist PSB0788. AR stimulation augmented IL-10-induced STAT3 phosphorylation in macrophages, and pharmacological inhibition or silencing of STAT3 using siRNA reduced the stimulatory effect of AR stimulation on TIMP-1 production. In contrast to its stimulatory effect on IL-10-induced STAT3 activation, adenosine inhibited IL-6-induced STAT3 phosphorylation and SAA3 expression. In conclusion, adenosine enhances IL-10-induced STAT3 signaling and M2c macrophage activation.
Keywords:
TIMP-1; alternative activation; arginase.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adenosine / immunology
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Adenosine / pharmacology*
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Adenosine A2 Receptor Agonists / pharmacology
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Aminopyridines / pharmacology
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Analgesics / immunology
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Analgesics / pharmacology*
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Animals
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Arginase / biosynthesis
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Arginase / genetics
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Arginase / immunology
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Cell Line
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Gene Expression Regulation
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Interleukin-10 / genetics
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Interleukin-10 / immunology*
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Interleukin-10 / metabolism
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Interleukin-13 / genetics
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Interleukin-13 / immunology
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Interleukin-13 / metabolism
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Interleukin-4 / genetics
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Interleukin-4 / immunology
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Interleukin-4 / metabolism
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Interleukin-6 / genetics
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Interleukin-6 / immunology
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Interleukin-6 / metabolism
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Macrophage Activation / drug effects*
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Macrophage Activation / genetics
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Macrophage Activation / immunology
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Macrophages / cytology
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Macrophages / immunology*
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Macrophages / metabolism
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Mice
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Mice, Knockout
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Phosphorylation / drug effects
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Phosphorylation / genetics
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Phosphorylation / immunology
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Receptor, Adenosine A2B / genetics
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Receptor, Adenosine A2B / immunology
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Receptor, Adenosine A2B / metabolism
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STAT3 Transcription Factor / genetics
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STAT3 Transcription Factor / immunology*
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STAT3 Transcription Factor / metabolism
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Serum Amyloid A Protein / biosynthesis
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Serum Amyloid A Protein / genetics
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Serum Amyloid A Protein / immunology
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Signal Transduction / drug effects*
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Signal Transduction / genetics
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Signal Transduction / immunology
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Tissue Inhibitor of Metalloproteinase-1 / biosynthesis
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Tissue Inhibitor of Metalloproteinase-1 / genetics
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Tissue Inhibitor of Metalloproteinase-1 / immunology
Substances
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Adenosine A2 Receptor Agonists
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Aminopyridines
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Analgesics
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BAY 60-6583
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IL10 protein, mouse
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Interleukin-13
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Interleukin-6
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Receptor, Adenosine A2B
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STAT3 Transcription Factor
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Saa3 protein, mouse
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Serum Amyloid A Protein
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Stat3 protein, mouse
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Timp1 protein, mouse
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Tissue Inhibitor of Metalloproteinase-1
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Interleukin-10
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Interleukin-4
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Arg1 protein, mouse
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Arginase
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Adenosine