The Adenosine System Selectively Inhibits TLR-Mediated TNF-α Production in the Human Newborn

Abstract

Human newborns are susceptible to microbial infection and mount poor vaccine responses, yet the mechanisms underlying their susceptibility are incompletely defined. We have previously reported that despite normal basal expression of TLRs and associated signaling intermediates, human neonatal cord blood monocytes demonstrate severe impairment in TNF-α production in response to triacylated (TLR 2/1) and diacylated (TLR 2/6) bacterial lipopeptides (BLPs). We now demonstrate that in marked contrast, BLP-induced synthesis of IL-6, a cytokine with anti-inflammatory and Th2-polarizing properties, is actually greater in neonates than adults. Remarkably, newborn blood plasma confers substantially reduced BLP-induced monocyte synthesis of TNF-α, while preserving IL-6 synthesis, reflecting the presence in neonatal blood plasma of a soluble, low molecular mass inhibitory factor (<10 kDa) that we identify as adenosine, an endogenous purine metabolite with immunomodulatory properties. The neonatal adenosine system also inhibits TNF-α production in response to whole microbial particles known to express TLR2 agonist activity, including Listeria monocytogenes, Escherichia coli (that express BLPs), and zymosan particles. Selective inhibition of neonatal TNF-α production is due to the distinct neonatal adenosine system, including relatively high adenosine concentrations in neonatal blood plasma and heightened sensitivity of neonatal mononuclear cells to adenosine A3 receptor-mediated accumulation of cAMP, a second messenger that inhibits TLR-mediated TNF-α synthesis but preserves IL-6 production. We conclude that the distinct adenosine system of newborns polarizes TLR-mediated cytokine production during the perinatal period and may thereby modulate their innate and adaptive immune responses.

Distinct phenotypic features of neonatal murine macrophages

“…Its increased expression might explain the robust activation of neonatal macrophages despite lower expression of TLR4 we observed. The important role of adenosine in neonatal macrophages and differences in their lipid and glucose metabolism was supported by an increased expression of factors such as adenosine deaminase, 24-dehydrocholesterol reductase, and glucose-6-phosphate dehydrogenase as shown in network No.3 (37). All these factors are also known to modulate the inflammatory response [45].…”

Le facteur d’inhibition de la migration des macrophages (MIF), un régulateur de la réponse immunitaire innée néonatale

“…Ces cellules produisent également moins de cytokines favorisant la différencia-tion des lymphocytes T CD4 + naïfs en cellules T helper de type 1 (T H 1) qui sont spécialisées dans la défense contre les pathogènes intracellulaires. Par contre, la production de cytokines favorisant la différenciation des cellules T CD4 + naïves en cellules T H 17, impliquées dans l'immunité des muqueuses, de même que la production de cytokines anti-inflammatoires est similaire voire plus élevée que chez l'adulte [4,5].…”

“…L'adénosine et les prostaglandines PGE 2 et PGF 2 sécrétées par le placenta sont également présentes à des concentrations élevées dans la circulation Pendant la grossesse, le placenta (en rouge) produit en abondance des hormones stéroïdiennes, de l'adénosine et des prostaglandines (dont PGE 2 ) qui gagnent la circulation foetale par l'intermédiaire de la veine ombilicale (flèche jaune). B. Les concentrations plasmatiques d'oestradiol, progestérone, adénosine, PGE 2 et MIF mesurées à la naissance chez des nouveau-nés à terme sains (barres bleues) sont supérieures à celles mesurées chez des adultes en bonne santé (barres vertes) [4,5,7]. Les concentrations d'oestradiol et de progestérone chez les adultes en bonne santé sont celles mesurées chez des femmes au cours de leur cycle menstruel [11].…”

“…Globalement, ces observations montrent sanguine des nouveau-nés. L'adénosine et la PGE 2 inhibent de façon sélective la production de TNF- par les monocytes [4,7]. L'environnement intra-utérin, à dominante anti-inflammatoire, favorise la tolérance aux antigènes maternels, préserve les organes en développement, prévient le déclenchement d'accouchements prématurés et facilite la tolé-rance aux micro-organismes qui colonisent la peau et les intestins après la naissance.…”

Obstacles to effective Toll-like receptor agonist therapy for hematologic malignancies

“…Adenosine can enter the tumor microenvironment through equilibrative nucleoside transporters (King et al, 2006) or be formed by extracellular ecto-phosphopyrases (such as CD39) and ecto-5 0 -nucleotidases (such as CD73) when necrotic cells spill their intracellular contents (Lasley et al, 1999). High levels of adenosine in the tumor microenvironment (Blay et al, 1997) may be a major obstacle to the development of TLR tolerization in cancer cells as adenosine is an especially strong negative regulator of TLR signaling, prevents TNF-a synthesis after initial TLR stimulation and accounts for poor responses of neonates to endotoxin in vivo (Levy et al, 2006).…”