Interferon-gamma–mediated tissue factor expression contributes to T-cell-mediated hepatitis through induction of hypercoagulation in mice

Katô, Junko; Okamoto, Takahiro; Motoyama, Hideki; Uchiyama, Ryosuke; Kirchhofer, Daniel; Rooijen, Nico van; Enomoto, Hirayuki; Nishiguchi, Shuhei; Kawada, Norifumi; Fujimoto, Jiro; Tsutsui, Hiroko

doi:10.1002/hep.26027

Cited by 63 publications

(78 citation statements)

References 31 publications

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“…Betulin reduces serum levels of IFN-γ, TNF-α, and IL-6 in mice with hepatitis Several lines of evidence suggest that IFN-γ [16,17] , TNF-α [18,19] , IL-4 [20] , and IL-17 [21,22] promote hepatic damage, whereas IL-10 [23] protects the liver from injury, and IL-6 [18] has varying effects depending on the stage of Con A-induced hepatitis at which it is present. To ascertain whether betulin interfered with the systemic levels of these cytokines, we examined the serum levels of IFN-γ, TNF-α, IL-2, IL-4, IL-6, IL-10, and IL-17 by using a CBA kit.…”

Section: Resultsmentioning

confidence: 99%

“…In Con A-induced hepatitis, the inflammatory response is responsible for liver damage and is mainly driven by proinflammatory Th1 cytokines. High levels of proinflammatory cytokines such as TNF-α [18,19] and IFN-γ [16] have been shown to promote the progress of this disease. In addition, neutralizing or knocking out the secretion of these cytokines leads to animal resistance to Con A-induced hepatic damage.…”

Section: Discussionmentioning

confidence: 99%

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Betulin from Hedyotis hedyotidea ameliorates concanavalin A-induced and T cell-mediated autoimmune hepatitis in mice

et al. 2016

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Hedyotis hedyotidea has been used in traditional Chinese medicine for the treatment of autoimmune diseases. However, the mechanisms underlying for the effect remain unknown. We previously showed that, among 11 compounds extracted from H hedyotidea, betulin produced the strongest suppressive effect on T cell activation. Here, we examined the hepatoprotective effects of betulin against acute autoimmune hepatitis in mice and the mechanisms underlying the effects. Freshly isolated mouse splenocytes were stimulated with concanavalin A (Con A, 5 μg/mL) in the presence of betulin, the cell proliferation was assessed with CSFE-dilution assay. Mice were injected with betulin (10, 20 mg· kg -1 ·d -1 , ip) for 3 d. One hour after the last injection, the mice were injected with Con A (15 mg/kg, iv) to induce acute hepatitis. Blood samples and liver tissues were harvested at 10 h after Con A injection, and serum transaminase levels and liver histopathology were detected; serum levels of proinflammatory cytokines, hepatic T lymphocyte ratios, and functional statuses of conventional T and NKT cells were also analyzed. Betulin (16 and 32 μmol/L) dose-dependently suppressed the proliferation of Con A-stimulated mouse splenocytes in vitro. In Con A-challenged mice, preinjection with betulin (20 mg· kg -1 ·d -1 ) significantly decreased the levels of proinflammatory cytokines IFN-γ, TNF-α and IL-6, and ameliorated liver injury. Furthermore, pretreatment with betulin (20 mg· kg -1 ·d -1 ) significantly inhibited the Con A-induced activation of NKT and conventional T cells, and decreased production of proinflammatory cytokines IFN-γ, TNF-α and IL-6 in these two cell populations. Betulin has immunomodulatory effect on overly activated conventional T and NKT cells and exerts hepatoprotective action in mouse autoimmune hepatitis. The findings provide evidence for the use of H hedyotidea and its constituent betulin in the treatment of autoimmune diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Betulin from Hedyotis hedyotidea ameliorates concanavalin A-induced and T cell-mediated autoimmune hepatitis in mice

et al. 2016

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“…To elucidate the cellular source for the high level of circulating IFN-γ and TNF-α, previous studies demonstrated that CD4 + T cells were the main source of increased IFN-γ Kato et al, 2013) and TNF-α (Kato et al, 2013) after Con A challenge. Our study demonstrated that DEX pretreatment inhibited IκBα and p65 phosphorylation in Con A-induced hepatitis.…”

Section: Discussionmentioning

confidence: 99%

Dexmedetomidine premedication attenuates concanavalin A-induced hepatitis in mice

Wang

Zou

et al. 2014

J. Toxicol. Sci.

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-Activated T cells selectively induced by concanavalin A (Con A) in liver are subsequent efficient resolution of inflammation. Activated T cells infiltrating in liver combined with pro-inflammatory cytokines are the major causes in Con A-induced liver injury. In our study, C57/BL mice were injected with Con A combined with dexmedetomidine or not. ALT and AST in blood and histopathology of liver were measured. T cell infiltration in liver was examined by flow cytometry and pro-inflammatory cytokines including IL-6, IL-10, TNF-α, and IFN-γ in blood were measured by ELISA. The mRNA level of CXCL10 was detected by RT-PCR and the protein level of NF-κB was measured by Western-blot. We found that dexmedetomidine alleviated Con A-induced liver injury by down-regulating levels of ALT and AST in blood and the severity of histopathology, which reflect the severity of hepatitis induced by Con A. In addition, pro-inflammatory cytokines in blood were attenuated by dexmedetomidine. Dexmedetomidine restrained the phosphorylation of NF-κB IκBα and P-65 dramatically which may participate in the regulation of cytokines secretion. Moreover, CXCL10 mRNA attenuated by dexmedetomidine in liver may result in the lower level of CD4 + T cells infiltration in liver. These results suggested that dexmedetomidine might be a potential compound in treating T cell-mediated liver injury.

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“…Inhibition of the coagulation cascade can potently rescue mice from Con A hepatitis without impairment in the induction of IFN-γ and TNF [54]. Very recently, we identified the cellular and molecular mechanisms for the development of Con A-induced acute prothrombotic liver failure [55]. …”

Section: Hypercoagulation-associated Acute Severe Hepatitismentioning

confidence: 99%

Importance of Kupffer Cells in the Development of Acute Liver Injuries in Mice

Tsutsui

Nishiguchi

2014

IJMS

Self Cite

125

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Kupffer cells reside within the liver sinusoid and serve as gatekeepers. They produce pro- and anti-inflammatory cytokines and other biologically important molecules upon the engagement of pattern recognition receptors such as Toll-like receptors. Kupffer cell-ablated mice established by in vivo treatment with clodronate liposomes have revealed many important features of Kupffer cells. In this paper, we review the importance of Kupffer cells in murine acute liver injuries and focus on the following two models: lipopolysaccharide (LPS)-induced liver injury, which is induced by priming with Propionibacterium acnes and subsequent challenge with LPS, and hypercoagulability-mediated acute liver failure such as that in concanavalin A (Con A)-induced hepatitis. Kupffer cells are required for LPS sensitization induced by P. acnes and are a major cellular source of interleukin-18, which induces acute liver injury following LPS challenge. Kupffer cells contribute to Con A-induced acute liver failure by initiating pathogenic, intrasinusoidal thrombosis in collaboration with sinusoidal endothelial cells. The mechanisms underlying these models may shed light on human liver injuries induced by various etiologies such as viral infection and/or abnormal metabolism.

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Interferon-gamma–mediated tissue factor expression contributes to T-cell-mediated hepatitis through induction of hypercoagulation in mice

Cited by 63 publications

References 31 publications

Betulin from Hedyotis hedyotidea ameliorates concanavalin A-induced and T cell-mediated autoimmune hepatitis in mice

Betulin from Hedyotis hedyotidea ameliorates concanavalin A-induced and T cell-mediated autoimmune hepatitis in mice

Dexmedetomidine premedication attenuates concanavalin A-induced hepatitis in mice

Importance of Kupffer Cells in the Development of Acute Liver Injuries in Mice

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