Control of Interferon‐alphaA by CD73: Implications for Mucosal Inflammation

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.