Interleukin-10 Attenuates Liver Fibrosis Exacerbated by Thermoneutrality

Abstract

Background: Crosstalk between brown adipose tissue (BAT) and the liver is receiving increasing attention. This study investigated the effect of BAT dysfunction by thermoneutral (TN) housing on liver fibrosis in mice and examined the effect of secreted factors from brown adipocytes on the activation of hepatic stellate cells (HSCs).Methods: The carbon tetrachloride (CCl4)-induced liver fibrosis mouse model was used to evaluate fibrotic changes in the livers of mice housed under standard and TN conditions. The effect of BAT on the activation of HSCs was examined using cultured cells treated with conditioned media from brown adipocytes.Results: Under TN conditions, mice with CCl4-induced liver fibrosis exhibited increased liver injury, collagen deposition, and alpha smooth muscle actin (α-SMA) expression in the liver compared with mice maintained at room temperature. The numbers of liver-infiltrating immune cells and T cells producing IL-17A and IFN-γ were also significantly increased in the livers of mice housed under TN conditions. Treatment of HSCs with conditioned media from brown adipocytes markedly attenuated HSC activation, as shown by down-regulated α-SMA expression at day 4, day 7 and day 10 of culture. At thermoneutrality, with CCl4 administration, IL-10-deficient mice exhibited more severe liver fibrosis than wild-type mice. Interestingly, conditioned media from IL-10-deficient brown adipocytes could up-regulate the expression of α-SMA and induce HSCs activation.Conclusions: BAT inactivation by thermoneutrality contributes to the activation of pro-inflammatory and pro-fibrotic pathways in mice with CCl4-induced liver fibrosis. Normal brown adipocytes secreted factors that impair the activation of HSCs, while this protective effect was lost in IL-10-deficient brown adipocytes. Thus, the BAT–liver axis may serve as a potential therapeutic target for liver fibrosis, and IL-10 may be a key factor regulating the activation of HSCs by BAT.

Olmesartan Improves Hepatic Sinusoidal Remodeling in Mice with Carbon Tetrachloride-Induced Liver Fibrosis

“…In the present study, the serum PDGF levels in mice in the liver fibrosis group were markedly increased, but olmesartan reduced PDGF expression to attenuate intrahepatic angiogenesis and fibrosis. In addition to regulating inflammatory mediators, IL-10 can promote HSC apoptosis and affect ECM remodeling, thereby inhibiting fibrosis [34][35][36]. We demonstrated that CCl 4 treatment lowered serum IL-10 levels in mice, while olmesartan increased IL-10 expression, indicating that olmesartan has potential anti-inflammatory and antifibrotic effects.…”

Carboxymethyl chitosan prolongs adenovirus‐mediated expression of IL‐10 and ameliorates hepatic fibrosis in a mouse model

“…Interleukin‐10 (IL10) is a cytokine produced by numerous activated immune cells such as B cells, mast cells, granulocytes, macrophages, DCs, and multiple T cell subsets, with plural and diverse cellular functions, and may play a beneficial preventive role in hepatic fibrosis 55,57–62 . As a proof‐of‐concept experiment, we sought to investigate whether the intrahepatic administration of CMC‐encapsulated Ad‐IL10 would prevent and/or alleviate hepatic fibrosis in the mouse model of CCl 4 ‐induced experimental hepatic fibrosis.…”

“…Interleukin‐10 (IL10) is a cytokine produced by numerous activated immune cells such as B cells, mast cells, granulocytes, macrophages, DCs, and multiple T cell subsets, with plural and diverse cellular functions, and may play a beneficial preventive role in hepatic fibrosis. 55 , 57 , 58 , 59 , 60 , 61 , 62 As a proof‐of‐concept experiment, we sought to investigate whether the intrahepatic administration of CMC‐encapsulated Ad‐IL10 would prevent and/or alleviate hepatic fibrosis in the mouse model of CCl 4 ‐induced experimental hepatic fibrosis. As shown in Figure 5a , three groups were set up: the fibrosis model only, the Ad‐IL10 group, and Ad‐IL10 + CMC group, in which all mice were treated with CCl 4 twice a week for 4 and 8 weeks, while the mice in the Ad‐IL10 and Ad‐IL10 + CMC groups also received intrahepatic injections of the Ad‐IL10 and Ad‐IL10 + CMC, respectively, once every 10 days for 4 and 8 weeks.…”

“…To provide a proof‐of‐concept study, we established a CCl 4 ‐induced experimental mouse model of chronic liver damage, and demonstrated that repeated intrahepatic injections, once every 10 days for up to six times, of Ad‐IL10 mixed with CMC effectively alleviated the development of hepatic fibrosis. It has been reported that IL10 exhibits anti‐hepatic fibrosis activity 55,57–62 . Since the pathogenic process of hepatic fibrosis is highly complex, it is conceivable that other contributing factors may be explored and targeted through Ad‐mediated gene therapy in combination with CMC.…”

“…It has been reported that IL10 exhibits anti‐hepatic fibrosis activity. 55 , 57 , 58 , 59 , 60 , 61 , 62 Since the pathogenic process of hepatic fibrosis is highly complex, it is conceivable that other contributing factors may be explored and targeted through Ad‐mediated gene therapy in combination with CMC. Collectively, our results strongly indicate that chitosan derivatives such as CMC provide apparent benefit for Ad‐mediated in vivo gene delivery by diminishing host immune response while allowing sustained transgene expression.…”