title: Amplification of the response to Toll-like receptor ligands by prolonged exposure to interleukin-6 in mice: implication for the pathogenesis of macrophage activation syndrome.
abstract: OBJECTIVE
  To investigate whether prolonged exposure to interleukin-6 (IL-6) affects the inflammatory response induced by Toll-like receptor (TLR) ligands.
  
  
  METHODS
  IL-6-transgenic mice and wild-type mice were stimulated with different TLR ligands; survival rates, blood cell counts, and biochemical parameters were analyzed. Murine splenic mononuclear cells and peritoneal macrophages were stimulated with lipopolysaccharide (LPS), lipoteichoic acid, poly(I-C), or CpG. Human macrophages were cultured for 4 days in the presence of IL-6 and then stimulated with LPS. Inflammatory cytokine expression was measured by enzyme-linked immunosorbent assay or reverse transcription-polymerase chain reaction. Activation of STAT-3, ERK-1/2 (MAPK), and p65 NF-κB was evaluated by Western blotting or confocal analysis.
  
  
  RESULTS
  Treatment of IL-6-transgenic mice with TLR ligands led to an increased fatality rate and elevated levels of IL-1β, tumor necrosis factor α (TNFα), IL-6, and IL-18. Macrophages from IL-6-transgenic mice produced increased levels of inflammatory cytokines, which were associated with increased phosphorylation of STAT-3 and ERK-1/2 and with increased NF-κB nuclear translocation. Human macrophages treated with IL-6 and then stimulated with LPS showed elevated levels of cytokines and similarly elevated signaling pathway activation. After LPS administration, IL-6-transgenic mice showed an increase in ferritin and soluble CD25 levels, as well as a decrease in platelet and neutrophil counts and in hemoglobin levels compared to wild-type mice.
  
  
  CONCLUSIONS
  Our findings indicate that prolonged exposure to IL-6 in vivo and in vitro leads to an exaggerated inflammatory response to TLR ligands. Hematologic and biochemical abnormalities in IL-6-transgenic mice treated with LPS show striking similarities to macrophage activation syndrome.
authors: Ospedale Pediatrico Bambino Gesù, Rome, Italy.
authors: Raffaele
authors: R
authors: Strippoli
authors: Francesco
authors: F
authors: Carvello
authors: Roberta
authors: R
authors: Scianaro
authors: Loredana
authors: L
authors: De Pasquale
authors: Marina
authors: M
authors: Vivarelli
authors: Stefania
authors: S
authors: Petrini
authors: Luisa
authors: L
authors: Bracci-Laudiero
authors: Fabrizio
authors: F
authors: De Benedetti
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006403:Hematologic Tests; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides / Q000276:immunology; D008136:Longevity / Q000187:drug effects; D055501:Macrophage Activation Syndrome / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D013154:Spleen / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D016207:Cytokines; D015850:Interleukin-6; D008024:Ligands; D008070:Lipopolysaccharides; D051193:Toll-Like Receptors