Inhibition of UII/UTR System Relieves Acute Inflammation of Liver through Preventing Activation of NF-κB Pathway in ALF Mice

Abstract

Urotensin II (UII) is implicated in immune inflammatory diseases through its specific high-affinity UT receptor (UTR). Enhanced expression of UII/UTR was recently demonstrated in the liver with acute liver failure (ALF). Here, we analysed the relationship between UII/UTR expression and ALF in lipopolysaccharide (LPS)/D-galactosamine (GalN)-challenged mice. Thereafter, we investigated the effects produced by the inhibition of UII/UTR system using urantide, a special antagonist of UTR, and the potential molecular mechanisms involved in ALF. Urantide was administered to mice treated with LPS/GalN. Expression of UII/UTR, releases of proinflammatory cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and interferon-γ (IFN-γ), and activation of nuclear factor κB (NF-κB) signaling pathway were assessed in the lethal ALF with or without urantide pretreatment. We found that LPS/GalN-challenged mice showed high mortality and marked hepatic inflammatory infiltration and cell apoptosis as well as a significant increase of UII/UTR expression. Urantide pretreatment protected against the injury in liver following downregulation of UII/UTR expression. A close relationship between the acutely flamed hepatic injury and UII/UTR expression was observed. In addition, urantide prevented the increases of proinflammatory cytokines such as TNF-α, IL-1β and IFN-γ, and activation of NF-κB signaling pathway induced by LPS/GalN in mice. Thus, we conclude that UII/UTR system plays a role in LPS/GalN-induced ALF. Urantide has a protective effect on the acutely inflamed injury of liver in part through preventing releases of proinflammatory cytokines and activation of NF-κB pathway.

Protective Role of Cannabinoid Receptor 2 Activation in Galactosamine/Lipopolysaccharide-Induced Acute Liver Failure through Regulation of Macrophage Polarization and MicroRNAs

“…2B). Because hepatocyte apoptosis is the major event that leads to ALF (Liang et al, 2014), and caspase-3 is a major mediator of apoptosis, we next studied the effect of JWH-133 upon the GalN/LPS1vehicle-triggered apoptosis in liver tissues by immunoblotting. Liver tissues isolated from mice 12 hours after GalN/LPS1vehicle injection showed a very significant increase in caspase-3 cleavage indicative of liver tissue damage by apoptosis (Fig.…”

“…The model triggers ALF through the binding of LPS to Toll-like receptor 4 (TLR4) on liver resident macrophages, the Kupffer cells (KCs), leading to their activation and secretion of a number of proinflammatory cytokines (Zhan et al, 2014). These cytokines provide a signal for the ensuing massive infiltration of immune cells in the liver and initiate apoptosis in the liver parenchyma, ultimately leading to ALF (Liang et al, 2014).…”

Urotensin II upregulates migration and cytokine gene expression in leukocytes of the African clawed frog, Xenopus laevis

“…It is well known that NF-jB in mammals plays a critical role in the activation of immune cells by upregulating the expression of many cytokines (e.g., IL-1, IL-2, IL-6, IL-12, TNF-a, IFN-c, and GM-CSF) essential to the immune response (Liang et al, 2013). UII increased the phosphorylation of NF-jB in lung adenocarcinoma A549 cells and induced the upregulation of cytokines such as IL-6 and TNFa (Zhou et al, 2012).…”

“…In addition, the interaction between the UII-UTR system and cytokines, which are released from innate immune cells and play key roles in the regulation of immune response, has been reported in pathologies such as fibrotic disorders (Dai et al, 2007(Dai et al, , 2011Tian et al, 2008). Liang and colleagues showed that the inhibition of the UII-UTR system with urantide reduced the serum levels of TNFa, IL-1b, and IFN-c in lipopolysaccharide (LPS)/D-galactosamine (GaIN)-challenged mice (Liang et al, 2013). However, the direct actions of UII on cytokine production in leukocytes remain to be elucidated even in mammals.…”

IRF3 is an important molecule in the UII/UT system and mediates immune inflammatory injury in acute liver failure

“…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 UT-specific antagonist urantide significantly inhibited UII/UT expression in the mouse liver, relieved inflammatory injury of the liver tissues, and down-regulated the levels of the pro-inflammatory cytokines TNF-α and IL-1β [16]. These results suggested that the UII/UT signaling system mediated LPS/D-GalN-induced inflammatory liver injury in ALF.…”