Interleukin-10 blunts the human inflammatory response to lipopolysaccharide without affecting the cardiovascular response

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Abstract
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. The authors conducted a randomized, placebo-controlled, double-blind trial. The study was conducted in a procedure room of an intensive-care unit. The study comprised 24 healthy male volunteers. 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. 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. 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.