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Abstract
The urotensin II (UII)/UII receptor (UT) system is closely related to immune inflammation. In acute liver failure (ALF), the UII/UT system can promote the production and release of proinflammatory cytokines, inducing an inflammatory injury response in liver tissue. However, the mechanism by which the hepatic UII/UT system promotes proinflammatory cytokine production and release is not clear. To solve this problem, we used primary Kupffer cells (KCs) as the model system in the current study. The results showed that after lipopolysaccharide (LPS) stimulation, KCs showed significantly increased expression and release of UII/UT and proinflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β). Pretreatment with urantide, which is a UT receptor antagonist, significantly inhibited the LPS-stimulated expression and release of UII/UT, TNF-α, and IL-1β by KCs. In addition, LPS stimulation induced nuclear p38 mitogen-activated protein kinase (MAPK) protein phosphorylation and expression of the nuclear nuclear factor κB (NF-κB) p65 subunit in KCs and enhanced the binding activity of NF-κB to DNA molecules, whereas urantide pretreatment significantly inhibited the LPS-stimulated nuclear expression and activity of these molecules in KCs. Therefore, our conclusion is that the UII/UT system mediates LPS-stimulated production and release of proinflammatory cytokine by KCs, and this mediating effect at least partially relies on the inflammatory signaling pathway molecules p38 MAPK and NF-κB.
Highlights
Acute liver failure (ALF) is a clinical syndrome characterized by severe acute liver tissue damage and rapid loss of liver function due to various factors [1]
To understand whether the urotensin II (UII)/UII receptor (UT) system is related to the liver immune inflammation, we studied UII/UT expression in Kupffer cells (KCs), which are the main hepatic innate immune cells
We found that after LPS stimulation, the expression levels of UII/UT as well as tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β) genes were significantly increased in KCs
Summary
Acute liver failure (ALF) is a clinical syndrome characterized by severe acute liver tissue damage and rapid loss of liver function due to various factors [1]. Our recent study using an ALF mouse model revealed that UII/UT was primarily expressed in the non-parenchymal cells of the liver (i.e., Kupffer cells (KCs) and endothelial cells) and that blocking UII signaling with the UT-specific antagonist urantide could prevent LPS-induced death in ALF mice, reduce liver inflammation injury, and significantly reduce the production and release of proinflammatory cytokines in the liver, including TNF-α, IL-1β, and IFN-γ [14]. The compound competitively antagonized UII-induced effects with pKB = 8.3±0.09 and displaced [125I]UII from specific binding at UII recombinant receptor (pKi = 8.3±0.04), and has been proposed as the most potent UT antagonist so far described [16] It suggests that the UII/UT system can mediate the occurrence of ALF by promoting the release of proinflammatory cytokines in the liver
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