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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
#MMPMID27042162
Rios EC
; Soriano FG
; Olah G
; Gerö D
; Szczesny B
; Szabo C
J Inflamm (Lond)
2016[]; 13
(?): 10
PMID27042162
show ga
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 ?g/ml) for 4 or 24 h, and then treated with a high concentration of LPS
(1 ?g/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-? 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.
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