Control of IFN-alphaA by CD73: implications for mucosal inflammation.

Abstract

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 alpha,beta-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-alphaA in cd73(-/-) mice and alpha,beta-methylene ADP-treated cd73(+/+) mice, compared with cd73(+/+) mice. Exogenous administration of recombinant IFN-alphaA partially protected TNBS-treated cd73(-/-) mice. Cytokine profiling revealed similar increases in both IFN-gamma and TNF-alpha 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-alphaA. Further cytokine profiling revealed that this IL-10 induction is preceded by a transient IFN-alphaA induction on day 2 after TNBS exposure. Together, these studies indicate a critical regulatory role for CD73-modulated IFNalphaA in the acute inflammatory phase of TNBS colitis, thereby implicating IFN-alphaA as a protective element of adenosine signaling during mucosal inflammation.

• Authors: Nancy A Louis, Andreas M Robinson, Christopher F MacManus, Jörn Karhausen, Melanie Scully, Sean P Colgan
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 180 Issue 6 Pg. 4246-55 (Mar 15 2008) ISSN: 0022-1767 [Print] United States
• PMID: 18322237 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Inflammation Mediators
• Interferon-alpha
• RNA, Messenger
• alpha,beta-methyleneadenosine 5'-diphosphate
• Interleukin-10
• Adenosine Diphosphate
• Trinitrobenzenesulfonic Acid
• 5'-Nucleotidase

Topics

• 5'-Nucleotidase (antagonists & inhibitors, biosynthesis, deficiency, physiology)
• Acute Disease
• Adenosine Diphosphate (administration & dosage, analogs & derivatives)
• Animals
• Colitis (chemically induced, immunology, pathology)
• Disease Progression
• Down-Regulation (immunology)
• Inflammation Mediators (physiology)
• Interferon-alpha (administration & dosage, antagonists & inhibitors, biosynthesis, genetics)
• Interleukin-10 (biosynthesis, deficiency, genetics)
• Intestinal Mucosa (immunology, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• RNA, Messenger (antagonists & inhibitors, biosynthesis)
• Trinitrobenzenesulfonic Acid (toxicity)