title: Hydrogen sulfide modulates chromatin remodeling and inflammatory mediator production in response to endotoxin, but does not play a role in the development of endotoxin tolerance.
abstract: BACKGROUND
  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. 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).
  
  
  METHODS
  To 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.
  
  
  RESULTS
  LPS 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.
  
  
  CONCLUSIONS
  In 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.
authors.affiliation: Department of Emergency Medicine, Universidade de São Paulo Medical School, São Paulo, Brazil.
authors.forename: Ester C S
authors.initials: EC
authors.lastname: Rios
authors.affiliation: Department of Emergency Medicine, Universidade de São Paulo Medical School, São Paulo, Brazil.
authors.forename: Francisco G
authors.initials: FG
authors.lastname: Soriano
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch, 601 Harborside Drive, Building 21, Room 4.202D, Galveston, TX 77555-1102 USA.
authors.forename: Gabor
authors.initials: G
authors.lastname: Olah
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch, 601 Harborside Drive, Building 21, Room 4.202D, Galveston, TX 77555-1102 USA.
authors.forename: Domokos
authors.initials: D
authors.lastname: Gerö
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch, 601 Harborside Drive, Building 21, Room 4.202D, Galveston, TX 77555-1102 USA.
authors.forename: Bartosz
authors.initials: B
authors.lastname: Szczesny
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch, 601 Harborside Drive, Building 21, Room 4.202D, Galveston, TX 77555-1102 USA.
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabo
keywords: Cytokines; Endotoxin; Hydrogen sulfide; Macrophages; Tolerance