Arctigenin protects against liver injury from acute hepatitis by suppressing immune cells in mice
Graphical abstract
Introduction
Liver diseases are very common in people [1]. Many etiologies can lead to liver damage, such as immune responses, which have been reported to play an important role in the pathogenesis of liver dysfunction [2]. In 1992, Tiegs et al. successfully induced immunological hepatitis in mice using concanavalin A (ConA) [3]. The administration of immunological inhibitors such as dexamethasone, cyclosporine A, and FK 506 (Fujimycin), could protect animals against liver injury [3]. More recently, the model has been widely used to investigate the etiopathogenesis, pathogenesis, and clinical treatment of immunological hepatitis in humans. Macrophages have been classically described as cells that phagocytose (engulf and then digest) cellular debris and pathogens, and this key activity is critical in the response to liver injury [1,4]. Hepatic macrophages, when activated, yield powerful chemical substances, such as reactive oxygen species, eicosanoids, nitric oxide, carbon monoxide, tumor necrosis factor-alpha (TNF-α), and other cytokines, which are involved in the early phase of liver inflammation and play important role in the innate and adaptive immune defenses [2]. Arctium lappa (Niubang) is a plant used in traditional Chinese herbal medicine that has been applied widely in China for the treatment of inflammatory conditions, such as syphilis, cough, anemopyretic cold, measles, and swelling of the throat [5]. Arctigenin is a bioactive component extracted from Arctium lappa [6], and it has been shown to have effective antioxidant, antiviral, anti-inflammatory, neuronal protection, and anti-cancer properties [[7], [8], [9], [10]]. There is a report that arctigenin inhibited human primary T lymphocyte proliferation by inhibiting the expression of interleukin (IL)-2 and interferon (IFN)-γ and by regulating immune responses in activated macrophages and lymphocytes, including TNF-α production and lymphocyte proliferation [11]. Recently, arctigenin was found to inhibit the differentiation of Th1 and Th17 cells in peripheral immune organs and in animal model of experimental autoimmune encephalomyelitis (EAE) [12]. Moreover, the application of arctigenin in liver diseases has been investigated. Previously, a study reported that arctigenin, as one of the cancer-specific phytochemicals, showed selective cytotoxicity to a liver cancer cell line (HepG2) and inhibited its proliferation [13]. Proliferation of activated hepatic stellate cells (HSCs) is vital for the development of fibrosis during liver injury. Arctigenin exhibited selective cytotoxic activity through the inhibition of platelet-derived growth factor-BB (PDGF-BB)-activated HSC proliferation, and it arrested the cell cycle at the G0/G1 phase, which could not be observed in normal human hepatocytes in vitro [14].
For a long time, we have been interested in the application of several herbal compounds for the treatment of various diseases [[15], [16], [17], [18], [19], [20]], including arctigenin [12]. In the present study, we established mouse model of acute hepatitis by ConA [20,21], investigated the anti-inflammatory effects of arctigenin on acute hepatitis, and explored the regulation of arctigenin in immune reactions. The results demonstrated that arctigenin exhibited anti-inflammatory effects on ConA-induced acute hepatitis by inhibition of T lymphocytes and macrophage activation.
Section snippets
Animals and cells
Six- to eight-week-old male BALB/c mice weighing 19–20 g were obtained from the Academy of Military Medical Sciences (Beijing, China). All of the animals were kept in the Tianjin Experimental Animal Center, living in a specific pathogen-free environment at 20–25 °C with adequate food and sufficient water. Before the experiments, the mice adapted to the new environment for 1 week and were then divided into several groups according to weight by a randomized grouping method. All of the mouse
Arctigenin protects mice against ConA-induced liver injury
To study the protective effects of arctigenin on ConA-induced acute liver injury in mice, a prophylactic protocol was performed (Fig. 1A). In the 20 μg/g ConA-induced acute hepatitis experiment, both 5 and 10 μg/g arctigenin administration obviously reduced the gross pathological changes in the livers, such as necrosis and congestion. The liver surface changed from rough to smooth (Fig. 1B), suggesting that ConA-induced liver dysfunction could be effectively prevented by arctigenin treatment.
Discussion
In the development of liver disease, massive hepatocellular death is considered to be the core event because it is accompanied by inflammatory cell infiltration and hepatic ischemic injury. Liver failure occurs when the rate and extent of hepatocellular death exceed the regenerative capacity of the liver. Some studies have indicated that arctigenin has a beneficial effect on liver diseases [13,14,22]. It has been reported that arctigenin exhibited selective cytotoxicity in hepatoma by the
Conflicts of interest
No potential conflicts of interest relevant to this article were reported.
Author contributions
H.W. and X.C. performed the experiments, collected data, analyzed the data and wrote the manuscript. J.Y., Y.C., Y.W., F.Y., and D.W. performed parts of the experiments and collected and analyzed the data. Q.Z., Z.X., W.H., Y.L., L.Z., D.N. and L.Y. contributed to the guidance of experiments and contributed to the final manuscript. R.Z. and Y.D. designed the study and contributed to the final manuscript. All of the authors reviewed the manuscript.
Acknowledgements
This work was supported by the National Natural Science Foundation of China through Grants No. 81272317, 81541032, 31600730, and 81602496; and the Natural Science Foundation of Tianjin through Grant Nos. 16JCYBJC24600 and 16JCYBJC24800.
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These authors contributed equally to this work.