title: Soluble ecto-5'-nucleotidase (5'-NT), alkaline phosphatase, and adenosine deaminase (ADA1) activities in neonatal blood favor elevated extracellular adenosine.
abstract: Extracellular adenosine, a key regulator of physiology and immune cell function that is found at elevated levels in neonatal blood, is generated by phosphohydrolysis of adenine nucleotides released from cells and catabolized by deamination to inosine. Generation of adenosine monophosphate (AMP) in blood is driven by cell-associated enzymes, whereas conversion of AMP to adenosine is largely mediated by soluble enzymes. The identities of the enzymes responsible for these activities in whole blood of neonates have been defined in this study and contrasted to adult blood. We demonstrate that soluble 5'-nucleotidase (5'-NT) and alkaline phosphatase (AP) mediate conversion of AMP to adenosine, whereas soluble adenosine deaminase (ADA) catabolizes adenosine to inosine. Newborn blood plasma demonstrates substantially higher adenosine-generating 5'-NT and AP activity and lower adenosine-metabolizing ADA activity than adult plasma. In addition to a role in soluble purine metabolism, abundant AP expressed on the surface of circulating neonatal neutrophils is the dominant AMPase on these cells. Plasma samples from infant observational cohorts reveal a relative plasma ADA deficiency at birth, followed by a gradual maturation of plasma ADA through infancy. The robust adenosine-generating capacity of neonates appears functionally relevant because supplementation with AMP inhibited whereas selective pharmacologic inhibition of 5'-NT enhanced Toll-like receptor-mediated TNF-α production in neonatal whole blood. Overall, we have characterized previously unrecognized age-dependent expression patterns of plasma purine-metabolizing enzymes that result in elevated plasma concentrations of anti-inflammatory adenosine in newborns. Targeted manipulation of purine-metabolizing enzymes may benefit this vulnerable population.
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Boston Children's Hospital, Boston, Massachusetts 02115; Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Matthew
authors.initials: M
authors.lastname: Pettengill
authors.affiliation: Harvard Medical School, Boston, Massachusetts 02115; Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215.
authors.forename: Simon
authors.initials: S
authors.lastname: Robson
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Boston Children's Hospital, Boston, Massachusetts 02115.
authors.forename: Megan
authors.initials: M
authors.lastname: Tresenriter
authors.affiliation: Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California 92037.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Millán
authors.affiliation: Harvard Medical School, Boston, Massachusetts 02115; Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215.
authors.forename: Anny
authors.initials: A
authors.lastname: Usheva
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Boston Children's Hospital, Boston, Massachusetts 02115; Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Taiese
authors.initials: T
authors.lastname: Bingham
authors.affiliation: Department of Pediatrics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Belderbos
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Boston Children's Hospital, Boston, Massachusetts 02115.
authors.forename: Ilana
authors.initials: I
authors.lastname: Bergelson
authors.affiliation: Vaccinology Theme Group, Medical Research Council Unit, Fajara, The Gambia; Department of Pediatrics, Imperial College London, London W2 IPG, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Burl
authors.affiliation: Vaccinology Theme Group, Medical Research Council Unit, Fajara, The Gambia; Department of Pediatrics, Imperial College London, London W2 IPG, United Kingdom.
authors.forename: Beate
authors.initials: B
authors.lastname: Kampmann
authors.affiliation: Experimental Medicine Program, Department of Medicine.
authors.forename: Laura
authors.initials: L
authors.lastname: Gelinas
authors.affiliation: Division of Infectious and Immunologic Diseases, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
authors.forename: Tobias
authors.initials: T
authors.lastname: Kollmann
authors.affiliation: Department of Pediatrics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
authors.forename: Louis
authors.initials: L
authors.lastname: Bont
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Boston Children's Hospital, Boston, Massachusetts 02115; Harvard Medical School, Boston, Massachusetts 02115. Electronic address: ofer.levy@childrens.harvard.edu.
authors.forename: Ofer
authors.initials: O
authors.lastname: Levy
mesh_terms: D015720:5'-Nucleotidase / Q000097:blood*; D000241:Adenosine / Q000097:blood*; D000243:Adenosine Deaminase / Q000097:blood*; D000328:Adult; D000375:Aging / Q000097:blood*; D000469:Alkaline Phosphatase / Q000097:blood*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D007231:Infant, Newborn; D007288:Inosine / Q000097:blood; D008297:Male
chemical_list: D007288:Inosine; D000469:Alkaline Phosphatase; D015720:5'-Nucleotidase; C548482:ADA protein, human; D000243:Adenosine Deaminase; D000241:Adenosine
keywords: ADP; AMP; ATP; Adenosine; Adenosine Receptor; Immunology; Infectious Diseases; Innate Immunity; Purine; Purinergic Agonists
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