title: Attenuation of monocyte proinflammatory cytokine responses to Neisseria meningitidis in children by erythropoietin.
abstract: Meningococcal disease is a leading infectious cause of death in children in industrialized countries. The induction of high levels of proinflammatory cytokines has been implicated in the pathogenesis of Neisseria meningitidis-related multi-organ failure. Here, we demonstrate that N. meningitidis serotypes A and B induce significantly higher levels of tumour necrosis factor (TNF)-alpha positive cells in vitro in infants and young children compared with adults (serotype A/B; infants: 64.9%/63.9%; children: 77.8%/64.3% versus adults: 27.7%/32%; P < 0.005). Serotype A induces also higher levels of interleukin (IL)-6 positive cells in neonates and infants compared with adults (serotype A; newborn 55.4%; infants 58.8% versus adults 49%; P < 0.05). Treatment with human recombinant erythropoietin in vitro resulted in significant attenuation of the N. meningitidis-induced proinflammatory response in all age groups (reduction rate of erythropoietin for IL-6 after stimulation with serotype B: newborn 28%, infants 15%, children 23% and adults 28% and for TNF-alpha after stimulation with serotype B: newborn 27%, infants 22%, children 20% and adults 28%; P < 0.05). We conclude that (i) Neisseria meningitidis induces a higher TNF-alpha response in infants and children compared with adults and (ii) erythropoietin was able to attenuate IL-6 and TNF-alpha production in all investigated age groups. These data may explain the high incidence of meningococcal infection in infants and makes erythropoietin a potentially attractive candidate for interventional strategies in an otherwise devastating course of the disease.
authors.affiliation: Department of Paediatrics, Medical University of Lübeck, Germany. schultz@paedia.ukl.mu-luebeck.de
authors.forename: C
authors.initials: C
authors.lastname: Schultz
authors.forename: J
authors.initials: J
authors.lastname: Zimmer
authors.forename: C
authors.initials: C
authors.lastname: Härtel
authors.forename: J
authors.initials: J
authors.lastname: Rupp
authors.forename: P
authors.initials: P
authors.lastname: Temming
authors.forename: T
authors.initials: T
authors.lastname: Strunk
mesh_terms: D000328:Adult; D000367:Age Factors; D002478:Cells, Cultured; D002675:Child, Preschool; D016207:Cytokines / Q000096:biosynthesis*; D004921:Erythropoietin / Q000276:immunology*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015850:Interleukin-6 / Q000096:biosynthesis; D008589:Meningococcal Infections / Q000276:immunology*; D009000:Monocytes / Q000276:immunology*; D009345:Neisseria meningitidis / Q000145:classification / Q000276:immunology*; D011994:Recombinant Proteins; D012703:Serotyping; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D016207:Cytokines; D015850:Interleukin-6; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D004921:Erythropoietin
references.citation: Blood. 1995 Mar 1;85(5):1341-7
references.pmid: 7858264
references.citation: Clin Exp Immunol. 2004 Jan;135(1):130-6
references.pmid: 14678274
references.citation: J Infect Dis. 1995 Apr;171(4):1057-60
references.pmid: 7706790
references.citation: J Pediatr. 2002 Jul;141(1):8-15
references.pmid: 12091844
references.citation: Mol Med. 2002 Aug;8(8):495-505
references.pmid: 12435860
references.citation: N Engl J Med. 2007 Sep 6;357(10):965-76
references.pmid: 17804841
references.citation: Infect Immun. 2002 Mar;70(3):1301-9
references.pmid: 11854214
references.citation: Lancet. 2004 Jan 17;363(9404):203-9
references.pmid: 14738793
references.citation: Infect Immun. 1999 May;67(5):2452-63
references.pmid: 10225908
references.citation: Acta Paediatr. 2008 Jan;97(1):16-20
references.pmid: 18052997
references.citation: Arch Dis Child Fetal Neonatal Ed. 2004 Jul;89(4):F364-6
references.pmid: 15210677
references.citation: Pediatrics. 2006 Oct;118(4):e979-84
references.pmid: 17015517
references.citation: Pediatr Res. 2002 Mar;51(3):317-22
references.pmid: 11861936
references.citation: Clin Exp Immunol. 2005 Dec;142(3):446-53
references.pmid: 16297156