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A by CD73: Implications for Mucosal Inflammation1
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* Neonatology Division and
Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115;
Division of Neonatal-Perinatal Medicine, Emory University School of Medicine, Atlanta, GA 30322;
Mucosal Inflammation Program, Division of Gastroenterology, University of Colorado Health Sciences Center, Denver, CO 80262; and
¶ Abteilung Anästhesiologie und Transfusionsmedizin, Universitätsklinik Tübingen, Tübingen, Germany
Inflammatory diseases influence tissue metabolism, altering regulation of extracellular adenine nucleotides, with a resultant protective influence of adenosine. Ecto-5'-nucleotidase (CD73) is a central surface enzyme generating extracellular adenosine. Thus, we hypothesized that CD73 is protective in mucosal inflammation as modeled by trinitrobenzene sulfonate (TNBS) colitis. Initial studies revealed a >3-fold induction of CD73 mRNA levels after TNBS colitis. Additionally, the severity of colitis was increased, as determined by weight loss and colonic shortening, in cd73–/– mice relative to cd73+/+ controls. Likewise, enteral administration of the selective CD73 inhibitor 
,β-methylene ADP to cd73+/+ mice resulted in a similar increase in severity of TNBS colitis. Gene array profiling of cytokine mRNA expression, verified by real-time PCR, revealed a >90% down-regulation of IFN-A in cd73–/– mice and ,β-methylene ADP-treated cd73+/+ mice, compared with cd73+/+ mice. Exogenous administration of recombinant IFN-A partially protected TNBS-treated cd73–/– mice. Cytokine profiling revealed similar increases in both IFN-
and TNF- mRNA in colitic animals, independent of genotype. However, IL-10 mRNA increased in wild-type mice on day 3 after TNBS administration, whereas cd73–/– mice mounted no IL-10 response. This IL-10 response was restored in the cd73–/– mice by exogenous IFN-A. Further cytokine profiling revealed that this IL-10 induction is preceded by a transient IFN-A induction on day 2 after TNBS exposure. Together, these studies indicate a critical regulatory role for CD73-modulated IFNA in the acute inflammatory phase of TNBS colitis, thereby implicating IFN-A as a protective element of adenosine signaling during mucosal inflammation.
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1 This work was supported by National Institutes of Health Grants DK50189, DE016191, HL60569, and DK62007 and by a grant from the Crohn’s and Colitis Foundation of America. S.P.C. holds the Kern Family Professorship of Medicine at the University of Colorado Health Sciences Center.
2 Address correspondence and reprint requests to Dr. Nancy A. Louis, Emory University School of Medicine, 2015 Uppergate Drive Northeast, Atlanta, GA 30322. E-mail address: nancy_louis{at}oz.ped.emory.edu
3 N.A.L. and A.M.R. contributed equally to this work.
4 Abbreviations used in this paper: TNBS, trinitrobenzene sulfonate; CD73, ecto-5'-nucleotidase; Ado, adenosine; APCP, ,β-methylene ADP; PMN, polymorphonuclear cell or neutrophil; A2AR, adenosine A2A receptor; A2BR, adenosine A2B receptor; pDC, plasmacytoid dendritic cells.
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