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Control of Interferon‐alphaA by CD73: Implications for Mucosal Inflammation
Author(s) -
Louis Nancy Anne,
Robinson Andreas Mark,
Karhausen Joern,
Scully Melanie,
Colgan Sean Patrick
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a131
Subject(s) - colitis , inflammation , extracellular , inflammatory bowel disease , immunology , medicine , cytokine , adenosine , pharmacology , chemistry , disease , biochemistry
Inflammatory diseases change tissue metabolism, resulting in alterations in extracellular adenine nucleotide regulation and a resultant protective influence of adenosine (Ado). We hypothesized that Ecto‐5′‐nucleotidase (CD73), a central surface enzyme in the generation of extracellular Ado, is protective in mucosal inflammation as modeled by TNBS colitis. Initial studies revealed a greater than 3‐fold increase in CD73 mRNA levels following induction of TNBS colitis. We further demonstrate more severe colitis, as determined by weight loss and colonic shortening, in cd73 − / − mice relative to cd73+/+ controls. Likewise, systemic administration of the selective CD73 inhibitor APCP to cd73+/+ mice resulted in a similar increase in severity of TNBS colitis. Gene array profiling of cytokine‐associated mRNA expression revealed a greater than 90% down‐regulation of IFNαA in cd73 − / − compared to cd73+/+ mice. Real‐time PCR verified this profound colonic IFNαA down‐regulation in both cd73 − / − mice and APCP‐treated cd73+/+ mice. Finally, exogenous administration of recombinant IFNαA partially protected cd73 − / − mice from disease severity in colitis. Together, these studies indicate a critical regulatory role for CD73‐modulated IFNαA in the acute inflammatory phase of TNBS colitis, and implicate IFNαA as a protective element of Ado signalling during mucosal inflammation.