Abstract
BackgroundPretreatment with low doses of LPS (lipopolysaccharide, bacterial endotoxin) reduces the pro-inflammatory response to a subsequent higher LPS dose, a phenomenon known as endotoxin tolerance. Moreover, hydrogen sulfide (H2S), an endogenous gaseous mediator (gasotransmitter) can exert anti-inflammatory effects. Here we investigated the potential role of H2S in the development of LPS tolerance. THP1 differentiated macrophages were pretreated with the H2S donor NaHS (1 mM) or the H2S biosynthesis inhibitor aminooxyacetic acid (AOAA, 1 mM).MethodsTo induce tolerance, cells were treated with a low concentration of LPS (0.5 μg/ml) for 4 or 24 h, and then treated with a high concentration of LPS (1 μg/ml) for 4 h or 24 h. In in vivo studies, male wild-type and CSE-/- mice were randomized to the following groups: Control (vehicle); Endotoxemic saline for 3 days before the induction of endotoxemia with 10 mg/kg LPS) mg/kg; Tolerant (LPS at 1 mg/kg for 3 days, followed LPS at 10 mg/kg). Animals were sacrificed after 4 or 12 h; plasma IL-6 and TNF-α levels were measured. Changes in histone H3 and H4 acetylation were analyzed by Western blotting.ResultsLPS tolerance decreased pro-inflammatory cytokine production. AOAA did not affect the effect of tolerance on reducing cytokine production. Treatment of the cells with the H2S donor reduced cytokine production. Induction of the tolerance increased the acetylation of H3; AOAA reduced histone acetylation. H2S donation increased histone acetylation. Tolerance did not affect the responses to H2S with respect to histone acetylation.ConclusionsIn conclusion, both LPS tolerance and H2S donation decrease LPS-induced cytokine production in vitro and modulate histone acetylation. However, endogenous, CSE-derived H2S does not appear to play a significant role in the development of LPS tolerance.
Highlights
IntroductionPretreatment with low doses of LPS (lipopolysaccharide, bacterial endotoxin) reduces the pro-inflammatory response to a subsequent higher LPS dose, a phenomenon known as endotoxin tolerance
Pretreatment with low doses of LPS reduces the pro-inflammatory response to a subsequent higher LPS dose, a phenomenon known as endotoxin tolerance
Cells exposed initially to low concentration of LPS followed by high concentration of LPS (Tolerance and Direct Challenge: Group TD) produced significant less interleukin 6 (IL-6) (Fig. 4b) and TNF-α (Fig. 5b) than the amount of the cytokines produced in the Direct Challenge Group (Group D), validating the development of tolerance in our experimental protocol
Summary
Pretreatment with low doses of LPS (lipopolysaccharide, bacterial endotoxin) reduces the pro-inflammatory response to a subsequent higher LPS dose, a phenomenon known as endotoxin tolerance. In the early phase of sepsis and septic shock there is an intense release of pro inflammatory mediators that can promote tissue injury and multiple organ dysfunction [3,4,5,6,7]. LPS tolerance downregulates the inflammatory response in septic shock while increasing the ability of a host to eliminate the pathogens; it exerts protective effects in several models of sepsis and polymicrobial infection [14,15,16,17,18]. Chromatin remodeling during the period of LPS tolerance development modifies gene transcription profile and regulates or silences a host of genes in response to a subsequent challenge [12, 13]. LPS tolerance modulates the production of reactive oxygen and nitrogen species (ROS/RNS) [16]
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