RETRACTED: Low-dose endotoxin elicits variability in the inflammatory response in healthy volunteers

Stephens, Robert; O’Malley, Catherine; Frumento, Robert J.; Mythen, Michael G.; Bennett‐Guerrero, Elliott

doi:10.1177/09680519050110040401

Cited by 2 publications

(1 citation statement)

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“…Subjects challenged with endotoxin at 0.1 ng/kg exhibited, on average, no response. These data support work by others demonstrating small and variable systemic inflammatory responses in subjects challenged with endotoxin at 0.25- or 0.3-ng/kg 34, 35 .…”

Section: Resultssupporting

confidence: 90%

Cellular Metabolic Regulators

Haimovich¹,

Zhang

Calvano

et al. 2014

Annals of Surgery

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Introduction The Toll like receptor 4 (TLR4) ligand endotoxin triggers robust systemic inflammatory responses in humans at doses > 1.0 ng/kg. In this study we tested the hypothesis that evidence of TLR4-induced responses would be detectable in leukocytes challenged with endotoxin doses that are below the threshold needed to trigger a characteristic systemic inflammatory phenotype in humans. Methods Subjects were challenged with endotoxin at 1, 0.5, or 0.1 ng/kg (n=5 per dose). Systemic responses were monitored for 24 hour. Blood samples, collected at designated interval for up to 24 hours post-challenge, were used to determine plasma cytokines levels, total and differential leukocyte counts, expression of leukocyte cell surface receptors, and changes in the leukocyte transcriptome. Western blotting was used to determine changes in leukocyte protein expression. Results We found that in vivo endotoxin at concentrations <1.0 ng/kg triggers weak and variable responses in humans. In marked contrast, we show that endotoxin at a concentration as low as 0.1 ng/kg triggers a transient decline in cellular ATP levels in leukocytes. This is associated with the appearance of a unique protein expression signature in leukocytes. The protein expression signature includes three prominent features: i) AMP-activated protein kinase subunit α (AMPKα) degradation, ii) increased HIF-1α expression, and iii) autophagy, collectively indicative of a regulated metabolic response. An indistinguishable response phenotype was observed in human leukocytes treated with endotoxin in vitro. Discussion These data demonstrate for the first time in humans that a TLR4 ligand concentration that is below the threshold needed to trigger clinically evident systemic inflammatory manifestations initiates a transient decline in ATP levels, AMPKα degradation, HIF-1α expression, and autophagy in leukocytes. This establishes that low-grade TLR4 activation exerts control over leukocyte metabolism in the absence of systemic inflammatory indicators.

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Section: Resultssupporting

confidence: 90%