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Sphingosine kinase 1 inhibition improves lipopolysaccharide/D-galactosamine-induced acute liver failure by inhibiting mitogen-activated protein kinases pathway.

Abstract：

BACKGROUND:Sphingosine kinase 1 (SphK1)/sphingosine-1-phosphate (S1P)/sphingosine-1-phosphate receptors (S1PRs) signaling plays a key role in inflammatory responses. Lei et al. showed that SphK1 inhibition presented a hepatoprotective effect on acute liver damage via decreasing hepatic high-mobility group box 1 (HMGB1) cytoplasmic translocation. OBJECTIVE:We aim to determine whether SphK1 or S1PRs inhibition improves lipopolysaccharide (LPS)/D-galactosamine (GalN)-induced acute liver failure by inhibiting the mitogen-activated protein kinases (MAPKs) pathway. METHODS:A mouse model of acute liver failure was induced by LPS/GalN. Male C57BL/6J mice (6-8 weeks) were randomly distributed into five groups: control group, LPS/GalN group, SphK1 inhibition group (LPS/GalN+SKI-5c), S1PR1 inhibition group (LPS/GalN+W146), and S1PR3 inhibition group (LPS/GalN+CAY10444). RESULTS:We confirmed the findings of Lei et al. that hepatic SphK1 expression was upregulated; serum transaminase activity (AST, ALT), as well as serum TNF-α and IL-6, were decreased by SphK1 inhibition. We further showed that the expression of S1PR1 and S1PR3 was augmented in response to LPS/GalN. SphK1 inhibition improves hepatic hemorrhage, and the activities of hepatic caspase-3 and myeloperoxidase (MPO). Furthermore, the activation of the MAPKs family (JNK, ERK and p38) was suppressed by SphK1 inhibition. However, S1PR1 or S1PR3 inhibition did not protect the mouse against liver damage, though S1PR1 or S1PR3 inhibition reduced serum TNF-α and IL-6, and partially attenuated the phosphorylation of the MAPKs signaling. CONCLUSIONS:SphK1 inhibition improves LPS/GalN-induced liver injury by inhibiting activation of MAPKs signaling.

journal_name

United European Gastroenterol J

journal_title

United European gastroenterology journal

authors

Tian T,Tian W,Yang F,Zhao R,Huang Q,Zhao Y

doi

10.1177/2050640616637968

subject

Has Abstract

pub_date

2016-10-01 00:00:00

pages

677-685

issue

eissn

2050-6406

issn

2050-6414

pii

10.1177_2050640616637968

journal_volume

pub_type

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Sphingosine kinase 1 inhibition improves lipopolysaccharide/D-galactosamine-induced acute liver failure by inhibiting mitogen-activated protein kinases pathway.