title: Persistent activation of nuclear factor kappa-B signaling pathway in patients with unstable angina and elevated levels of C-reactive protein evidence for a direct proinflammatory effect of azide and lipopolysaccharide-free C-reactive protein on human monocytes via nuclear factor kappa-B activation.
abstract: OBJECTIVE
  Our study investigated: 1) the contribution of nuclear factor kappa-B (NF-kappaB) signaling pathway to the enhanced inflammatory response observed in unstable angina (UA) patients with elevated levels of C-reactive protein (CRP); and 2) whether CRP may have direct proinflammatory effects via NF-kappaB activation.
  
  
  BACKGROUND
  Unstable angina patients with elevated CRP have enhanced inflammatory response and increased risk of persistent instability, myocardial infarction, and death.
  
  
  METHODS
  We studied 28 patients with history of UA and persistently elevated CRP (>3 mg/l) followed for 24 months and free of symptoms for at least 6 months (group 1), 14 patients with history of UA and low CRP (group 2), and 24 patients with chronic stable angina and low CRP (group 3). Peripheral blood monocytes were analyzed for spontaneous NF-kappaB activation and interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha production. To assess the direct proinflammatory effects of CRP, monocytes from 8 healthy subjects were stimulated in vitro with increasing doses of CRP (5 to 10 to 25 microg/ml), lipopolysaccharide (LPS) (1 to 10 ng/ml), or both.
  
  
  RESULTS
  Spontaneous NF-kappaB activation in vivo was demonstrated in 82% of group 1 versus 14% of group 2 and 21% of group 3 patients (p < 0.001). Interleukin-6 and TNF-alpha production was significantly correlated with the NF-kappaB activation status (r = 0.55, p < 0.001 and r = 0.53, p = 0.006, respectively). Patients with NF-kappaB activation had recurrence of acute coronary events (60% vs. 28%; p = 0.017). C-reactive protein induced a significant but modest in vitro NF-kappaB activation in human monocytes (p = 0.002). Coincubation with LPS produced a greater-than-additive response (p < 0.01 vs. CRP and LPS alone).
  
  
  CONCLUSIONS
  Nuclear factor kappa-B activation might represent a mechanism by which CRP amplifies and perpetuates the inflammatory component of acute coronary syndromes and influences the clinical outcome.
authors.affiliation: Institute of Cardiology, Catholic University, Rome, Italy. gliuzzo@hotmail.com
authors.forename: Giovanna
authors.initials: G
authors.lastname: Liuzzo
authors.forename: Matteo
authors.initials: M
authors.lastname: Santamaria
authors.forename: Luigi M
authors.initials: LM
authors.lastname: Biasucci
authors.forename: Michela
authors.initials: M
authors.lastname: Narducci
authors.forename: Valeria
authors.initials: V
authors.lastname: Colafrancesco
authors.forename: Annalisa
authors.initials: A
authors.lastname: Porto
authors.forename: Salvatore
authors.initials: S
authors.lastname: Brugaletta
authors.forename: Michela
authors.initials: M
authors.lastname: Pinnelli
authors.forename: Vittoria
authors.initials: V
authors.lastname: Rizzello
authors.forename: Attilio
authors.initials: A
authors.lastname: Maseri
authors.forename: Filippo
authors.initials: F
authors.lastname: Crea
mesh_terms: D000328:Adult; D000368:Aged; D000789:Angina, Unstable / Q000276:immunology* / Q000378:metabolism; D001386:Azides / Q000494:pharmacology; D002097:C-Reactive Protein / Q000378:metabolism* / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism*; D012016:Reference Values; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D001386:Azides; D018836:Inflammation Mediators; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein