Mechanisms of concanavalin A-induced cytokine synthesis by hepatic stellate cells: Distinct roles of interferon regulatory factor-1 in liver injury

Abstract

Concanavalin A (ConA)‐induced liver injury in mice has been used extensively as a model to understand the role of immune cells. However, perisinusoidal hepatic stellate cells (HSCs), the primary cell type of liver fibrosis, were recently found to orchestrate ConA‐induced liver damage directly and by influencing recruitment and characteristics of immune cells. HSC‐released interferon‐β (IFNβ) and increased hepatic expression of a transcription factor, interferon regulatory factor 1 (IRF1), were determined to be major components of ConA‐induced liver injury. The aim of this study was to delineate the mechanisms of the actions of ConA on HSCs with specific focus on IRF1/IFNβ axis. HSCs and hepatocytes isolated from WT and IRF1−/− mice were used. HSCs were found to rapidly internalize FITC‐labeled ConA; internalized ConA was greatly concentrated in the perinuclear region. ConA increased the expression and nuclear translocation of IRF1 and NF‐κB in wild type (WT) HSCs and the expression of TNFα, IFNβ and CXCL1. These effects of ConA were abrogated in HSCs isolated from IRF1−/− mice. ConA induced JAK/STAT signaling in HSCs, and inhibitors of this signaling pathway ameliorated ConA‐induced IRF1 expression/nuclear translocation as well as cytokine/chemokine production. Finally, ConA‐stimulated WT but not IRF1−/− HSCs induced apoptosis of WT hepatocytes. Conversely, ConA‐stimulated WT HSCs were unable to induce apoptosis of IRF1−/− hepatocytes. Our findings suggest that IRF1 plays a dual role in ConA‐induced liver injury. On the one hand, ConA stimulates the synthesis of the mediators of hepatocyte injury through JAK/STAT signaling involving IRF1. On the other hand, IRF1 nuclear translocation in hepatocytes induced by ConA‐stimulated HSCs instigates apoptosis. While this mechanistic evaluation is performed using ConA, the findings could be relevant to liver injury due to lectins in the food products. In conclusion, HSC can be a potential therapeutic target for acute liver damage of various etiologies including lectins. Support or Funding Information This work was supported by a VA Merit Review Award 1IO1BX001174 to CRG. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Acupuncture stimulation attenuates TNF-α production via vagal modulation in the concanavalin A model of hepatitis

“…T lymphocytes produce lymphokines and also activate antigen-presenting cells such as macrophages. 17 Given that ConA treatment in experimental animals induces systemic inflammation in addition to pathological changes in several types of liver cells, including Kupffer cells and stellate cells, 18–20,21 we assumed that the ConA animal model would be useful to examine the regulatory effects of an acupuncture intervention which has, in theory, regulatory effects on the whole body. 21 We applied acupuncture stimulation at ST36, which has been shown to have regulatory effects on gastrointestinal and cardiovascular function, as well as pain regulation in relation to cancer, 22,23 and investigated its regulatory effects on the production of TNF-α.…”

Pro- and Anti-fibrogenic Functions of Gram-Negative Bacterial Lipopolysaccharide in the Liver

“…LPS stimulates the synthesis of both endothelin-1 and nitric oxide by HSCs, and LPS-induced vascular resistance of the previously normal liver is mitigated by endothelin receptor antagonism (47). HSCs also demonstrate remarkable ability to recruit inflammatory and immune cells, and influence their survival and functions (22,23,(38)(39)(40)(48)(49)(50)(51)(52)(53)(54). Furthermore, evidence has emerged showing an important role of HSCs in liver regeneration and hepatocellular carcinoma (55)(56)(57)(58).…”

“…Kupffer cells produce IL13 and not IL10 under basal conditions, and LPS stimulates secretion of IL10 but not of IL13 from them (141)(142)(143). HSCs also produce IL10 spontaneously, which is strongly stimulated by LPS (22,50). Such increased production of IL10 and IL13 can be yet another pathway of limiting liver fibrosis.…”

“…LPS stimulates IFNβ expression in HSCs (22,49,52) and it is likely that this can be an autocrine-inhibitory loop to reduce fibrosis. Interestingly, HSC-released IFNβ was found to be a major cytokine to cause autophagy in hepatocytes as a cell survival mechanism (Figure 5), but it could also induce acute liver injury through activation of IRF1 signaling in mice upon concanavalin A challenge (49,50,52).…”

PPARγ/NF‐κB and TGF‐β1/Smad pathway are involved in the anti‐fibrotic effects of levo‐tetrahydropalmatine on liver fibrosis

“…Our previous studies demonstrated that L‐THP could suppress apoptosis and autophagy in the presence of liver injury induced by concanavalin A (ConA) and hepatic ischaemia and reperfusion (IR) 27,28 . ConA injection and hepatic IR can both result in the activation of HSCs 29,30 . Moreover, dl‐tetrahydropalmatine (dl‐THP), another active component of Corydalis yanhusuo , was reported to ameliorate CCl4‐induced liver injury in mice by inhibiting hepatic lipoperoxidation 31…”