title: LPS- and LTA-induced expression of IL-6 and TNF-α in neonatal and adult blood: role of MAPKs and NF-κB.
abstract: As nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) seem to be critical mediators in the inflammatory response, we studied the effects of lipopolysaccharide (LPS) and lipoteichoic acid (LTA) on (a) the activation of NF-κB and MAPKs and (b) the expression of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) with or without the specific inhibitors of these intracellular signal transduction pathways in neonatal cord and adult blood. TNF-α and IL-6 concentrations showed a sharp increase in the supernatants of cord and adult whole blood after stimulation. TNF-α concentrations were significantly higher, whereas IL-6 concentrations were tendentially lower in adult blood after stimulation. Stimulation with LPS or LTA resulted in a significantly decreased activation of p38 MAPK in neonatal compared with adult blood. Although LTA failed to induce additional ERK1/2 phosphorylation, LPS stimulation mediated the moderately increased levels of activated ERK1/2 in neonatal monocytes. The addition of the p38 MAPK inhibitor SB202190 significantly decreased IL-6 and TNF-α production upon LPS or LTA stimulation. Furthermore, the inhibition of ERK1/2 was able to reduce LPS-stimulated TNF-α production in neonatal blood. We conclude that p38 MAPK as well as ERK1/2 phosphorylation is crucially involved in LPS activation and could explain the differences in early cytokine response between neonatal and adult blood.
authors.affiliation: Department of Neonatology, University Children's Hospital, Medical School, University of Heidelberg, 69120 Heidelberg, Germany ; Department of Neonatology, Catholic Children's Hospital Wilhelmstift, 22149 Hamburg, Germany.
authors.forename: Lutz
authors.identifier: 0000-0003-3683-2274
authors.initials: L
authors.lastname: Koch
authors.affiliation: Department of Neonatology, University Children's Hospital, Medical School, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: David
authors.identifier: 0000-0002-7289-1346
authors.initials: D
authors.lastname: Frommhold
authors.affiliation: Department of Neonatology, University Children's Hospital, Medical School, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Buschmann
authors.affiliation: Department of Neonatology, University Children's Hospital, Medical School, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Navina
authors.initials: N
authors.lastname: Kuss
authors.affiliation: Department of Neonatology, University Children's Hospital, Medical School, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Poeschl
authors.affiliation: Department of Neonatology, University Children's Hospital, Medical School, University of Heidelberg, 69120 Heidelberg, Germany ; Clinic of Pediatrics, SLK-Kliniken Heilbronn, 74078 Heilbronn, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Ruef
mesh_terms: D000328:Adult; D005260:Female; D005312:Fetal Blood / Q000378:metabolism; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D007231:Infant, Newborn; D015850:Interleukin-6 / Q000097:blood*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000737:chemistry*; D020935:MAP Kinase Signaling System; D009000:Monocytes / Q000166:cytology; D016328:NF-kappa B / Q000097:blood*; D010766:Phosphorylation; D011247:Pregnancy; D011725:Pyridines / Q000737:chemistry; D015398:Signal Transduction; D013682:Teichoic Acids / Q000737:chemistry*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C508600:IL6 protein, human; D007093:Imidazoles; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011725:Pyridines; D013682:Teichoic Acids; D014409:Tumor Necrosis Factor-alpha; C009900:lipoteichoic acid; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole