title: Neonatal plasma polarizes TLR4-mediated cytokine responses towards low IL-12p70 and high IL-10 production via distinct factors.
abstract: Human neonates are highly susceptible to infection, which may be due in part to impaired innate immune function. Neonatal Toll-like receptor (TLR) responses are biased against the generation of pro-inflammatory/Th1-polarizing cytokines, yet the underlying mechanisms are incompletely defined. Here, we demonstrate that neonatal plasma polarizes TLR4-mediated cytokine production. When exposed to cord blood plasma, mononuclear cells (MCs) produced significantly lower TLR4-mediated IL-12p70 and higher IL-10 compared to MC exposed to adult plasma. Suppression by neonatal plasma of TLR4-mediated IL-12p70 production, but not induction of TLR4-mediated IL-10 production, was maintained up to the age of 1 month. Cord blood plasma conferred a similar pattern of MC cytokine responses to TLR3 and TLR8 agonists, demonstrating activity towards both MyD88-dependent and MyD88-independent agonists. The factor causing increased TLR4-mediated IL-10 production by cord blood plasma was heat-labile, lost after protein depletion and independent of lipoprotein binding protein (LBP) or soluble CD14 (sCD14). The factor causing inhibition of TLR4-mediated IL-12p70 production by cord blood plasma was resistant to heat inactivation or protein depletion and was independent of IL-10, vitamin D and prostaglandin E2. In conclusion, human neonatal plasma contains at least two distinct factors that suppress TLR4-mediated IL-12p70 production or induce IL-10 or production. Further identification of these factors will provide insight into the ontogeny of innate immune development and might identify novel targets for the prevention and treatment of neonatal infection.
authors.affiliation: Department of Pediatrics, University Medical Center Utrecht, Utrecht, The Netherlands. m.belderbos@umcutrecht.nl
authors.forename: Mirjam E
authors.initials: ME
authors.lastname: Belderbos
authors.forename: Ofer
authors.initials: O
authors.lastname: Levy
authors.forename: Femke
authors.initials: F
authors.lastname: Stalpers
authors.forename: Jan L
authors.initials: JL
authors.lastname: Kimpen
authors.forename: Linde
authors.initials: L
authors.lastname: Meyaard
authors.forename: Louis
authors.initials: L
authors.lastname: Bont
mesh_terms: D000328:Adult; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D005312:Fetal Blood / Q000378:metabolism*; D006801:Humans; D007231:Infant, Newborn; D016753:Interleukin-10 / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000096:biosynthesis*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008297:Male; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D010949:Plasma / Q000378:metabolism*; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000378:metabolism*; D051200:Toll-Like Receptor 8 / Q000378:metabolism; D014807:Vitamin D / Q000378:metabolism
chemical_list: C508609:IL10 protein, human; D018950:Lipopolysaccharide Receptors; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; C495344:TLR3 protein, human; C495345:TLR4 protein, human; C495349:TLR8 protein, human; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051200:Toll-Like Receptor 8; D016753:Interleukin-10; D014807:Vitamin D; D018664:Interleukin-12; D015232:Dinoprostone