Abstract
The urotensin II/urotensin receptor (UII/UT) system can mediate inflammatory liver injury in acute liver failure (ALF); however; the related mechanism is not clear. In this study, we confirmed that lipopolysaccharide/D-galactosamine (LPS/D-GalN) induced up-regulation of liver interferon regulatory factor 3 (IRF3) in ALF mice, whereas the UT antagonist urantide inhibited the up-regulated liver IRF3. LPS stimulation induced IRF3 transcription and nuclear translocation and promoted the secretion of interleukin-6 (IL-6), interferon (IFN)-β, and IFN-γ in Kupffer cells (KCs); these effects in LPS-stimulated KCs were inhibited by urantide. Knockdown of IRF3 using an adenovirus expressing an IRF3 shRNA inhibited IFN-β transcription and secretion as well as tumor necrosis factor (TNF)-α and IL-1β secretion from LPS-stimulated KCs; additionally, IL-10 transcription and secretion were promoted in response to LPS. However, LPS-stimulated TNF-α and IL-1β mRNA was not affected in the KCs. The IRF3 shRNA also did not have a significant effect on the NF-κB p65 subunit and p38MAPK protein phosphorylation levels in the nuclei of LPS-stimulated KCs. Therefore, IRF3 expression and activation depended on the signal transduction of the UII/UT system, and played important roles in UII/UT-mediated immune inflammatory injury in the liver but did not affect NF-κB and p38 MAPK activity.
Highlights
Acute liver failure (ALF) is a liver tissue injury disease that has an immune-mediated inflammatory reaction as its main feature [1]
Urantide inhibited the interferon regulatory factor 3 (IRF3) protein expression induced by LPS/D-GalN. These results suggest that the urotensin II (UII)/UT signaling system mediates the LPS/D-GalN-induced up-regulation of IRF3 expression in liver tissues in ALF mice
Kupffer cell (KC) were treated with UII or urantide 0.5 h before LPS stimulation
Summary
Acute liver failure (ALF) is a liver tissue injury disease that has an immune-mediated inflammatory reaction as its main feature [1]. The vasoactive peptide substance urotensin II (UII) was shown to possess significant inflammatory activity. Studies showed that UII could function with UT to promote the aggregation of monocytes and macrophages at inflammatory injury sites and to promote the expression of adhesion molecules and chemokines and the release of inflammatory cytokines [810]. Patients with inflammatory vascular injury diseases such as atherosclerosis, chronic inflammatory cardiac injury diseases, immune-mediated inflammatory kidney injury diseases, and chronic inflammatory liver injury diseases all have high levels of UII secretion in the blood [11,12,13,14]. Our recent study showed that LPS/D-GalN induced an abnormal elevation of UII expression and secretion and UT expression in the livers of ALF experimental mice. The application of the UTspecific antagonist urantide significantly inhibited UII/
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