Abstract
Background Liver ischaemia-reperfusion injury (IRI) remains a problem in liver transplantation. Interleukin-4 (IL-4) has been found to reduce liver IRI, but the exact mechanism remains unclear. Methods Donor livers were infused with recombinant IL-4 or normal saline during cold storage, and the hepatocellular apoptosis and the inflammatory response were detected. The effect of IL-4 treatment on Kupffer cells (KCs) polarization and expression of the STAT6-JMJD3 pathway was evaluated in vivo and in vitro. KCs in donor livers were depleted by clodronate liposome treatment or JMJD3 was inhibited by GSK-J4 before liver transplantation to determine whether the protective effect of IL-4 treatment was dependent on KCs. Results IL-4 treatment decreased sALT and sAST levels and alleviated hepatocellular apoptosis and inflammation at 6 h after liver transplantation. IL-4 treatment induced KCs alternatively activated (M2) polarization in vitro. KCs in donor livers were depleted by clodronate liposome treatment or JMJD3 was inhibited by GSK-J4 before liver transplantation to determine whether the protective effect of IL-4 treatment was dependent on KCs. in vivo and in vitro. KCs in donor livers were depleted by clodronate liposome treatment or JMJD3 was inhibited by GSK-J4 before liver transplantation to determine whether the protective effect of IL-4 treatment was dependent on KCs. Conclusions IL-4 treatment-induced KCs M2 polarization was dependent on the STAT6-JMJD3 pathway and protected liver grafts from IRI after liver transplantation.
Highlights
With better disease control in patients before liver transplantation (LT), refined operative techniques, better organ preservation, and immunotherapy, the survival rate of recipients has improved by 60% in the last 20 years
Liver ischaemia-reperfusion injury (IRI) is a dynamic process with complicated mechanisms, such as sterile inflammation, oxidative stress, hepatocyte apoptosis, and activation of Kupffer cells, which begins during hepatic ischaemia and is further strengthened during reperfusion [3]
To explore whether IL-4 treatment could attenuate rat liver IRI after liver transplantation (LT), liver and serum samples were collected at 6 hours after liver transplantation, the peak of hepatocellular damage in this model [20]
Summary
With better disease control in patients before liver transplantation (LT), refined operative techniques, better organ preservation, and immunotherapy, the survival rate of recipients has improved by 60% in the last 20 years. Liver IRI is a dynamic process with complicated mechanisms, such as sterile inflammation, oxidative stress, hepatocyte apoptosis, and activation of Kupffer cells, which begins during hepatic ischaemia and is further strengthened during reperfusion [3]. E effect of IL-4 treatment on Kupffer cells (KCs) polarization and expression of the STAT6-JMJD3 pathway was evaluated in vivo and in vitro. IL-4 treatment induced KCs alternatively activated (M2) polarization in vitro and in vivo, and the expression of STAT6 and JMJD3 was increased. JMJD3 knockdown abolished KCs M2 polarization and reduced the antiapoptotic and anti-inflammatory effects induced by IL-4 treatment in vitro. The protection of IL-4 treatment against IRI induced by liver transplantation was significantly reduced after the depletion of KCs or the inhibition of JMJD3 in donor livers. IL-4 treatment-induced KCs M2 polarization was dependent on the STAT6-JMJD3 pathway and protected liver grafts from IRI after liver transplantation
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