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* Transplant and Immunobiology Research Centers, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
Department of Neurology, Boston University School of Medicine, Boston, MA 02118; and
Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
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-
production via adenosine A2aR-mediated signaling; blocking of HO-1 by RNA interference abrogated the effects of adenosine and NECA on TNF-. 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 F.H.B. and L.E.O. contributed equally to this work.
2 Address correspondence and reprint requests to Dr. Leo E. Otterbein, Beth Israel Deaconess Medical Center, 99 Brookline Avenue, Suite 370G, Boston, MA 02215. E-mail address: lotterbe{at}bidmc.harvard.edu
3 Abbreviations used in this paper: HO-1, heme oxygenase-1; 2-CADO, 2-chloradenosine; Ad-EGFP, adenovirus for enhanced GFP; Ad-HO-1, adenovirus for HO-1; BMDM, bone marrow-derived macrophage; CHO, Chinese hamster ovary; EGFP, enhanced GFP; EHNA, erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride; HA, hemagglutinin; NECA, 5'-N-ethylcarboxamidoadenosine; RT, room temperature; siRNA, small interfering RNA.
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