title: Interleukin-10 blunts the human inflammatory response to lipopolysaccharide without affecting the cardiovascular response.
abstract: OBJECTIVE
  The objective of this study was to assess the efficacy of variations in dose and timing of administration of recombinant human IL-10 (rhIL-10) on inflammatory and cardiovascular responses in a human endotoxemia model of sepsis.
  
  
  METHODS
  The authors conducted a randomized, placebo-controlled, double-blind trial.
  
  
  METHODS
  The study was conducted in a procedure room of an intensive-care unit.
  
  
  METHODS
  The study comprised 24 healthy male volunteers.
  
  
  METHODS
  Interventions consisted of intravenous administration of rhIL-10 at 1, 10, or 25 microg/kg either 2 mins or 2 hrs before Escherichia coli lipopolysaccharide (4 ng/kg) or placebo.
  
  
  RESULTS
  The placebo group receiving lipopolysaccharide alone demonstrated significant, time-dependent changes in vital signs, white blood cell counts, inflammatory cytokine/cortisol levels, and hemodynamic/cardiovascular (including echocardiographic) parameters over the duration of the study. rhIL-10, administered immediately before (concurrent) lipopolysaccharide resulted in decreased temperature and heart rate responses as well as decreased serum levels of proinflammatory cytokines (tumor necrosis factor-alpha, IL-6), IL-1 receptor antagonist, cortisol, and total leukocytes/neutrophils compared with lipopolysaccharide alone. Dose-dependent effects were absent. In contrast, rhIL-10 administration 2 hrs before endotoxin augmented the endotoxin-induced IL-beta and IL-1 receptor antagonist response. rhIL-10 failed to modulate major cardiovascular responses (cardiac output, stroke volume index, ejection fraction, peak systolic pressure/end-systolic volume ratio) to endotoxin in both study groups as assessed by echocardiography.
  
  
  CONCLUSIONS
  Concurrent administration of rhIL-10 suppresses the human inflammatory/stress response but has no effect on the hemodynamic/cardiovascular response to endotoxin. Early administration of rhIL-10 can potentially augment elements of the cytokine inflammatory response to lipopolysaccharide. These findings suggest significant limitations of rhIL-10 as a potential immunomodulatory therapy for sepsis.
authors.affiliation: Division of Cardiovascular Disease and Critical Care Medicine, Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL, USA.
authors.forename: Anand
authors.initials: A
authors.lastname: Kumar
authors.forename: Sergio
authors.initials: S
authors.lastname: Zanotti
authors.forename: Gene
authors.initials: G
authors.lastname: Bunnell
authors.forename: Kalim
authors.initials: K
authors.lastname: Habet
authors.forename: Ramon
authors.initials: R
authors.lastname: Añel
authors.forename: Alex
authors.initials: A
authors.lastname: Neumann
authors.forename: Mary
authors.initials: M
authors.lastname: Cheang
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: David
authors.initials: D
authors.lastname: Cutler
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Parrillo
mesh_terms: D000293:Adolescent; D000328:Adult; D016207:Cytokines / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004926:Escherichia coli; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000503:physiopathology; D018836:Inflammation Mediators / Q000097:blood; D016753:Interleukin-10 / Q000008:administration & dosage*; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D011994:Recombinant Proteins / Q000008:administration & dosage; D018805:Sepsis / Q000188:drug therapy / Q000503:physiopathology*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D016753:Interleukin-10