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Published on: April 21, 2015
Control of IFN-alphaA by CD73: implications for mucosal inflammation
Nancy A Louis1, Andreas M Robinson, Christopher F MacManus
1Neonatology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. nancy_louis@oz.ped.emory.edu
Journal of Immunology (Baltimore, Md. : 1950)
|March 7, 2008
Summary
Ecto-5'-nucleotidase (CD73) plays a protective role in trinitrobenzene sulfonate (TNBS) colitis by modulating interferon-alphaA (IFN-alphaA). Loss of CD73 or its inhibition exacerbates colitis, highlighting CD73-IFN-alphaA signaling in mucosal inflammation.
Area of Science:
- Immunology
- Gastroenterology
- Molecular Biology
Background:
- Inflammatory diseases alter tissue metabolism and extracellular adenine nucleotide regulation.
- Adenosine exerts a protective influence in inflammation.
- Ecto-5'-nucleotidase (CD73) generates extracellular adenosine, making it a key enzyme in this pathway.
Purpose of the Study:
- To investigate the protective role of CD73 in trinitrobenzene sulfonate (TNBS)-induced colitis, a model of mucosal inflammation.
- To determine the molecular mechanisms, specifically the involvement of interferon-alphaA (IFN-alphaA), in CD73-mediated protection.
Main Methods:
- Utilized CD73 knockout (cd73(-/-)) and wild-type (cd73(+/+)) mice in a TNBS colitis model.
- Administered a selective CD73 inhibitor (alpha,beta-methylene ADP) to wild-type mice.
- Analyzed disease severity (weight loss, colonic shortening) and quantified cytokine mRNA expression (IFN-alphaA, IFN-gamma, TNF-alpha, IL-10) using gene array profiling and real-time PCR.
Main Results:
- TNBS colitis severity was increased in cd73(-/-) mice and in wild-type mice treated with a CD73 inhibitor.
- IFN-alphaA mRNA levels were significantly down-regulated (>90%) in cd73(-/-) mice and inhibitor-treated mice.
- Exogenous IFN-alphaA partially protected cd73(-/-) mice, and restored IL-10 response, which was preceded by transient IFN-alphaA induction.
Conclusions:
- CD73 plays a critical protective role in the acute inflammatory phase of TNBS colitis.
- CD73-modulated IFN-alphaA is a key regulatory element in this protective pathway.
- IFN-alphaA acts as a protective mediator within the adenosine signaling cascade during mucosal inflammation.
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