title: Immaturity of infection control in preterm and term newborns is associated with impaired toll-like receptor signaling.
abstract: The impaired infection control related to the functional immaturity of the neonatal immune system is an important cause of infection in preterm newborns. We previously reported that constitutive Toll-like receptor (TLR) 4 expression and cytokine secretion on lipopolysaccharide (LPS) stimulation increases with gestational age. Here, we analyzed constitutive monocyte TLR2 expression and evaluated the expression profiles of the proximal downstream adapter molecule myeloid differentiation factor 88 (MyD88). We further investigated activation of protein kinases p38 and extracellular regulated kinsase (ERK) 1/2 in CD14 monocytes after ex vivo stimulation with bacterial TLR ligands (LPS and lipoteichoic acid [LTA]). The functional outcome of the stimulation was determined by cytokine secretion. Monocytes from 31 preterm newborns (<30 weeks of gestation, n=16; 30-37 weeks of gestation, n=15), 10 term newborns, and 12 adults were investigated. In contrast to TLR4 expression, TLR2 levels did not differ between age groups. However, MyD88 levels were significantly lower in preterm newborns. Activation of p38 and ERK1/2 was impaired in all newborn age groups after stimulation with TLR-specific ligands. Accordingly, after LTA stimulation, the levels of interleukin (IL)-1 beta , IL-6, and IL-8 cytokine production were substantially lower (P<.001) in preterm newborns than in adults. The reduced functional response to bacterial cell wall components appears to be part of the functional immaturity of the neonatal immune system and might predispose premature newborns to bacterial infection.
authors.affiliation: Department of Pediatrics, Division of Neonatology, Inborn Errors and Intensive Care, Medical University of Vienna, A-1090 Vienna, Austria.
authors.forename: Kambis
authors.initials: K
authors.lastname: Sadeghi
authors.forename: Angelika
authors.initials: A
authors.lastname: Berger
authors.forename: Michaela
authors.initials: M
authors.lastname: Langgartner
authors.forename: Andrea-Romana
authors.initials: AR
authors.lastname: Prusa
authors.forename: Michael
authors.initials: M
authors.lastname: Hayde
authors.forename: Kurt
authors.initials: K
authors.lastname: Herkner
authors.forename: Arnold
authors.initials: A
authors.lastname: Pollak
authors.forename: Andreas
authors.initials: A
authors.lastname: Spittler
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Forster-Waldl
mesh_terms: D000328:Adult; D000375:Aging / Q000276:immunology*; D005260:Female; D005312:Fetal Blood / Q000166:cytology / Q000276:immunology; D018507:Gene Expression Regulation, Developmental; D005865:Gestational Age; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology / Q000502:physiology*; D007231:Infant, Newborn / Q000276:immunology*; D007234:Infant, Premature / Q000276:immunology*; D009000:Monocytes / Q000276:immunology*; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D011247:Pregnancy; D015398:Signal Transduction / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D053594:Myeloid Differentiation Factor 88; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors