CD73-dependent regulation of interferon αA and interleukin-10 in the inflamed mucosa.
The ecto-5'-nucleotidase, CD73, catalyzes the rate-limiting step in the phosphohydrolysis of ATP to adenosine, and is a critical regulator of the balance between adenosine and its nucleotide precursors. Each of these classes of mediators signal through their independent receptor families to regulate downstream inflammatory signaling. CD73 activity is primarily regulated at the level of transcription in response to the oxygen-sensing transcription factor HIF1, and its tissue-specific expression correlates negatively with oxygen tension. HIF1-dependent induction of CD73 contributes to the protective effects of hypoxia in the inflamed intestinal mucosa. These beneficial effects of CD73 have largely been attributed to downstream adenosine signaling through its tissue-specific receptors. In addition, adenosine signaling has been directly implicated in the protective effects of hypoxic preconditioning against acute hypoxic or ischemic insults. However, recent work has demonstrated that CD73-/- animals lack the ability to produce interferon (IFN) αA, either at baseline or in response to inflammation. Furthermore, this IFNαA deficiency is associated with the inability to elaborate interleukin (IL)-10-dependent anti-inflammatory signaling. It remains unclear whether interruption of IFNαA and IL-10 signaling in the absence of CD73 activity results from a deficiency of its product adenosine or an accumulation of its substrate nucleotides. Current evidence for adenosine- and nucleotide-mediated mechanisms of tissue inflammation is reviewed below.
Division of Neonatal-Perinatal Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
Ilya
I
Sotnikov
Nancy A
NA
Louis
D015720:5'-Nucleotidase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D016898:Interferon-alpha / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological
D016898:Interferon-alpha; D016753:Interleukin-10; D015720:5'-Nucleotidase