Interleukin-10 blunts the human inflammatory response to lipopolysaccharide without affecting the cardiovascular response.
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.
Kumar
Anand
A
Division of Cardiovascular Disease and Critical Care Medicine, Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL, USA.
Zanotti
Sergio
S
Bunnell
Gene
G
Habet
Kalim
K
Añel
Ramon
R
Neumann
Alex
A
Cheang
Mary
M
Dinarello
Charles A
CA
Cutler
David
D
Parrillo
Joseph E
JE
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*
D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D016753:Interleukin-10