Control of IFN-alphaA by CD73: implications for mucosal inflammation.
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.
Louis
Nancy A
NA
Neonatology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. nancy_louis@oz.ped.emory.edu
Robinson
Andreas M
AM
MacManus
Christopher F
CF
Karhausen
Jörn
J
Scully
Melanie
M
Colgan
Sean P
SP
D015720:5'-Nucleotidase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D000208:Acute Disease; D000244:Adenosine Diphosphate / Q000008:administration & dosage / Q000031:analogs & derivatives; D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D018450:Disease Progression; D015536:Down-Regulation / Q000276:immunology; D018836:Inflammation Mediators / Q000502:physiology*; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D016753:Interleukin-10 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D007413:Intestinal Mucosa / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity
D018836:Inflammation Mediators; D016898:Interferon-alpha; D012333:RNA, Messenger; C523965:alpha,beta-methyleneadenosine 5'-diphosphate; D016753:Interleukin-10; D000244:Adenosine Diphosphate; D014302:Trinitrobenzenesulfonic Acid; D015720:5'-Nucleotidase