Cross-regulation of carbon monoxide and the adenosine A2a receptor in macrophages
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Cross-regulation of carbon monoxide and the adenosine A2a receptor in macrophages. / Haschemi, Arvand; Wagner, Oswald; Marculescu, Rodrig; Wegiel, Barbara; Robson, Simon C; Gagliani, Nicola; Gallo, David; Chen, Jiang-Fan; Bach, Fritz H; Otterbein, Leo E.
In: J IMMUNOL, Vol. 178, No. 9, 01.05.2007, p. 5921-9.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Cross-regulation of carbon monoxide and the adenosine A2a receptor in macrophages
AU - Haschemi, Arvand
AU - Wagner, Oswald
AU - Marculescu, Rodrig
AU - Wegiel, Barbara
AU - Robson, Simon C
AU - Gagliani, Nicola
AU - Gallo, David
AU - Chen, Jiang-Fan
AU - Bach, Fritz H
AU - Otterbein, Leo E
PY - 2007/5/1
Y1 - 2007/5/1
N2 - Adenosine and heme oxygenase-1 (HO-1) exert a wide range of anti-inflammatory and immunomodulatory actions, making them crucial regulatory molecules. Despite the diversity in their modes of action, the similarity of biological effects of adenosine and HO-1 led us to hypothesize a possible interrelationship between them. We assessed a potential role for HO-1 in the ability of adenosine or 5'-N-ethylcarboxamidoadenosine (NECA), a stable adenosine analog, to modify the response of LPS-stimulated macrophages. Adenosine and NECA markedly induced HO-1 and blocked LPS-induced TNF-alpha production via adenosine A2aR-mediated signaling; blocking of HO-1 by RNA interference abrogated the effects of adenosine and NECA on TNF-alpha. HO-1 overexpression or exposure to carbon monoxide (CO), a product of HO-1 enzymatic activity, resulted in augmented A2aR mRNA and protein levels in RAW264.7 cells and primary macrophages. The induction of A2aR expression by HO-1 or CO resulted in an increase in the sensitivity to the anti-inflammatory effects of adenosine and NECA, which was lost in macrophages isolated from A2aR-deficient mice. Moreover, a decrease in cAMP levels upon NECA stimulation of naive macrophages was counterbalanced by CO exposure to up-regulate A2aR levels. This implies adenosine receptor isoform switch as a selective modification in macrophage phenotype. Taken together, these data suggest the existence of a positive feedback loop among adenosine, HO-1, CO, and the A2aR in the chronological resolution of the inflammatory response.
AB - Adenosine and heme oxygenase-1 (HO-1) exert a wide range of anti-inflammatory and immunomodulatory actions, making them crucial regulatory molecules. Despite the diversity in their modes of action, the similarity of biological effects of adenosine and HO-1 led us to hypothesize a possible interrelationship between them. We assessed a potential role for HO-1 in the ability of adenosine or 5'-N-ethylcarboxamidoadenosine (NECA), a stable adenosine analog, to modify the response of LPS-stimulated macrophages. Adenosine and NECA markedly induced HO-1 and blocked LPS-induced TNF-alpha production via adenosine A2aR-mediated signaling; blocking of HO-1 by RNA interference abrogated the effects of adenosine and NECA on TNF-alpha. HO-1 overexpression or exposure to carbon monoxide (CO), a product of HO-1 enzymatic activity, resulted in augmented A2aR mRNA and protein levels in RAW264.7 cells and primary macrophages. The induction of A2aR expression by HO-1 or CO resulted in an increase in the sensitivity to the anti-inflammatory effects of adenosine and NECA, which was lost in macrophages isolated from A2aR-deficient mice. Moreover, a decrease in cAMP levels upon NECA stimulation of naive macrophages was counterbalanced by CO exposure to up-regulate A2aR levels. This implies adenosine receptor isoform switch as a selective modification in macrophage phenotype. Taken together, these data suggest the existence of a positive feedback loop among adenosine, HO-1, CO, and the A2aR in the chronological resolution of the inflammatory response.
KW - Adenosine
KW - Adenosine-5'-(N-ethylcarboxamide)
KW - Animals
KW - Carbon Monoxide
KW - Cells, Cultured
KW - Down-Regulation
KW - Heme Oxygenase-1
KW - Interleukin-10
KW - Interleukin-12
KW - Lipopolysaccharides
KW - Macrophages
KW - Mice
KW - RNA Interference
KW - RNA, Messenger
KW - Receptor, Adenosine A2A
KW - Tumor Necrosis Factor-alpha
KW - Journal Article
M3 - SCORING: Journal article
C2 - 17442976
VL - 178
SP - 5921
EP - 5929
JO - J IMMUNOL
JF - J IMMUNOL
SN - 0022-1767
IS - 9
ER -