Superoxide produced by Kupffer cells is an essential effector in concanavalin A–induced hepatitis in mice

Nakashima, Hiroyuki; Kinoshita, Manabu; Nakashima, Masahiro; Habu, Yoshiko; Shono, Shinjiro; Uchida, Takefumi; Shinomiya, Nariyoshi; Seki, Shu

doi:10.1002/hep.22561

Cited by 90 publications

(122 citation statements)

References 40 publications

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“…In mice, concanavalin A (ConA) injection is a paradigm for T cell-dependent hepatitis, although macrophages and NK and NKT cells are also essential (26)(27)(28)(29)(30). In nontreated wild-type mice, JUNB expression was not detectable in the liver by immunohistochemistry (IHC).…”

Section: Junb Is Upregulated In Human and Mouse Liver Hepatitismentioning

confidence: 99%

JUNB/AP-1 controls IFN-γ during inflammatory liver disease

Thomsen¹,

Bakiri²,

Hasenfuss³

et al. 2013

J. Clin. Invest.

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Understanding the molecular pathogenesis of inflammatory liver disease is essential to design efficient therapeutic approaches. In hepatocytes, the dimeric transcription factor c-JUN/AP-1 is a major mediator of cell survival during hepatitis, although functions for other JUN proteins in liver disease are less defined. Here, we found that JUNB was specifically expressed in human and murine immune cells during acute liver injury. We analyzed the molecular function of JUNB in experimental models of hepatitis, including administration of concanavalin A (ConA) or α-galactosyl-ceramide, which induce liver inflammation and injury.

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Section: Junb Is Upregulated In Human and Mouse Liver Hepatitismentioning

confidence: 99%

JUNB/AP-1 controls IFN-γ during inflammatory liver disease

Thomsen¹,

Bakiri²,

Hasenfuss³

et al. 2013

J. Clin. Invest.

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“…Con-A- (Nakashima et al, 2008) and APAP-induced hepatitis (Ayoub et al, 2004;Saito et al, 2010) mouse models were used to evaluate the efficacy of SH-Man-HSA as a CD68…”

Section: Discussionmentioning

confidence: 99%

“…Con-A-and APAP-induced liver injury mouse model was produced as previously reported (Ayoub et al, 2004;Nakashima et al, 2008;Saito et al, 2010). The animal experiment protocol is shown in Supplemental Figs.…”

Section: /Cd206mentioning

confidence: 99%

“…1 KC to produce TNF that interacts with the TNF receptor on the CD68 1 KC to produce ROS (Nakashima et al, 2008;Kinoshita et al, 2010). The possibility that the ROS-scavenging activity of SH-Man-HSA might be mediated via the inhibition of TNF or IFN-g cannot be completely excluded.…”

Section: /Cd206mentioning

confidence: 99%

“…Moreover, ROS produced by CD68 1 KC have been identified as an aggravating factor for the onset and progression of hepatitis in a concanavalin-A (Con-A)-induced hepatitis mouse model (Nakashima et al, 2008). In addition, mice that were pretreated with gadolinium chloride (GdCl 3 ), a KC inhibitor, especially CD68…”

Section: Introductionmentioning

confidence: 99%

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Polythiol-Containing, Recombinant Mannosylated-Albumin Is a Superior CD68⁺/CD206⁺Kupffer Cell–Targeted Nanoantioxidant for Treatment of Two Acute Hepatitis Models

Maeda¹,

Hirata²,

Watanabe³

et al. 2014

J Pharmacol Exp Ther

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Since reactive oxygen species (ROS) derived from Kupffer cells (KC), especially CD681 KC, play a key role in the induction of hepatic oxidative stress and injuries, we developed a polythiolatedand mannosylated human serum albumin (SH-Man-HSA), which functions as a novel nanoantioxidant for delivering thiol to CD68 1 KC. In vitro electron paramagnetic resonance coupled with pharmacokinetics and immunohistochemical studies showed that SH-Man-HSA possessed powerful radical-scavenging activity and rapidly and selectively delivered thiols to the liver via mannose receptor (CD206) on CD68 1 cells. SH-Man-HSA significantly improved the survival rate of concanavalin-A (Con-A)-treated mice. Moreover, SH-Man-HSA exhibited excellent hepatoprotective functions, not by decreasing tumor necrosis factor or interferon-g production that is closely associated with Con-A-induced hepatitis, but by suppressing ROS production.Interestingly, the protective effect of SH-Man-HSA was superior to N-acetyl cysteine (NAC). This could be attributed to the difference in the inhibition of hepatic oxidative stress between the two antioxidants depending on their potential for thiol delivery to the liver. Similar results were also observed for acetaminophen (APAP)-induced hepatopathy models. Flow cytometric data further confirmed that an increase in F4/80 1 /ROS 1 cells was dramatically decreased by SH-Man-HSA. The administration of SH-Man-HSA at 4 hours following a Con-A or APAP injection also exhibited a profound hepatoprotective action against these hepatitis models, whereas this was not observed for NAC. It can be concluded therefore that SH-Man-HSA has great potential for use in a rescue therapy for hepatopathy as a nanoantioxidant because of its ability to efficiently and rapidly deliver thiols to CD68

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Retinoic acid alleviates Con A‐induced hepatitis and differentially regulates effector production in NKT cells

et al. 2012

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IntroductionLiver damage induced by various agents, such as viral infection, results in serious problems accompanied by an excessive immune response [1]. Uncontrolled severe responses in the liver by immune cells are observed in diverse animal models, including Con A-induced hepatitis. Following the administration of Con A, T cells, granulocytes, and Kupffer cells infiltrate into the liver, resulting in the death of hepatocytes [2][3][4]. NKT cells are responsible Correspondence: Prof. Chang-Yuil Kang e-mail: cykang@snu.ac.kr for liver injury in this model [5][6][7][8][9][10]. NKT cells are a distinct T-cell subset with an invariant T-cell receptor (TCR) that recognizes glycolipids loaded on the cell-surface protein CD1d, and they rapidly secrete cytokines upon stimulation [11][12][13][14]. In Con A-induced liver injury, inflammatory cytokines, such as IFN-γ, TNF-α, and IL-4, from NKT cells are pathogenic [5,7,9,10]. In addition, a specific ligand of NKT cells, α-GalCer, can induce liver injury mediated by FasL and TNF-α rather than . Although NKT cells are critical to induce both Con A-and α-GalCer-induced liver injury, their pathologic mechanisms are different from each other.www.eji-journal.eu1686 Kyoo-A Lee et al. Eur. J. Immunol. 2012. 42: 1685-1694 Retinoic acid (RA), an active metabolite of vitamin A, regulates various diseases through anti-tumor and anti-inflammatory effects [18,19]. RA is associated with anti-inflammatory effects in diverse diseases [20]. RA also enhances T-cell effector responses and is critical in vaccine responses [21][22][23][24][25]. These contradictory findings imply that the exact physiological function of RA remains to be discovered. RA promotes the proliferation and activation of NKT cells indirectly in vitro by increasing CD1d expression in APCs [26][27][28]. However, the direct effects of RA on NKT cells and NKT cell-dependent diseases in vivo have not been examined. In the current study, we observed that RA differentially regulates NKT cell-mediated hepatitis and cytokine production by NKT cells. Our results suggest the selective regulatory effects and the therapeutic potential of RA in NKT cell-dependent diseases. Results RA regulates Con A-induced hepatitis and differentially regulates cytokine levels in serumTo determine the effect of RA itself, we injected RA directly into normal mice, and liver injury was induced by injecting Con A. The RA-treated group had a 100% survival rate, whereas the entire control group succumbed to the lethal dose (30 mg/kg) several hours after the Con A injection (Fig. 1A). In addition, when the ALT activity was measured in animals with nonlethal (20 mg/kg) Con A-induced hepatitis, significantly less ALT activity was observed in the RA-treated group (Fig. 1B). And also, liver histology showed massive necrosis in vehicle-treated mice, but in RA-treated mice, the liver tissue maintained the structure (Fig. 1C). Treatment with disulfiram, a blocking agent of RALDH that synthesizes RA, aggravated the survival rate and serum ALT activity, indicat...

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Superoxide produced by Kupffer cells is an essential effector in concanavalin A–induced hepatitis in mice

Cited by 90 publications

References 40 publications

JUNB/AP-1 controls IFN-γ during inflammatory liver disease

JUNB/AP-1 controls IFN-γ during inflammatory liver disease

Polythiol-Containing, Recombinant Mannosylated-Albumin Is a Superior CD68⁺/CD206⁺Kupffer Cell–Targeted Nanoantioxidant for Treatment of Two Acute Hepatitis Models

Retinoic acid alleviates Con A‐induced hepatitis and differentially regulates effector production in NKT cells

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Superoxide produced by Kupffer cells is an essential effector in concanavalin A–induced hepatitis in mice

Cited by 90 publications

References 40 publications

JUNB/AP-1 controls IFN-γ during inflammatory liver disease

JUNB/AP-1 controls IFN-γ during inflammatory liver disease

Polythiol-Containing, Recombinant Mannosylated-Albumin Is a Superior CD68+/CD206+Kupffer Cell–Targeted Nanoantioxidant for Treatment of Two Acute Hepatitis Models

Retinoic acid alleviates Con A‐induced hepatitis and differentially regulates effector production in NKT cells

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Polythiol-Containing, Recombinant Mannosylated-Albumin Is a Superior CD68⁺/CD206⁺Kupffer Cell–Targeted Nanoantioxidant for Treatment of Two Acute Hepatitis Models