MicroRNA-122 Inhibits the Production of Inflammatory Cytokines by Targeting the PKR Activator PACT in Human Hepatic Stellate Cells

Nakamura, Masato; Sasaki, Reina; Haga, Yuki; Jiang, Xia; Wu, Shuang; Nakamoto, Shingo; Yokosuka, Osamu

doi:10.1371/journal.pone.0144295

Cited by 37 publications

(34 citation statements)

References 56 publications

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“…Cell death, including apoptosis, seems important in the progression of NAFLD and NASH (Figure 1 ). Recently, several inhibitors of apoptosis have been suggested as potential treatments for NASH (Table 1 )[ 112 - 124 ]. Clinical trials for the treatment of NASH are currently being conducted[ 125 ] and some are targeting apoptosis in NASH patients.…”

Section: Discussionmentioning

confidence: 99%

Apoptosis and non-alcoholic fatty liver diseases

Kanda

Matsuoka

Yamazaki

et al. 2018

WJG

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219

145

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The number of patients with nonalcoholic fatty liver diseases (NAFLD) including nonalcoholic steatohepatitis (NASH), has been increasing. NASH causes cirrhosis and hepatocellular carcinoma (HCC) and is one of the most serious health problems in the world. The mechanism through which NASH progresses is still largely unknown. Activation of caspases, Bcl-2 family proteins, and c-Jun N-terminal kinase-induced hepatocyte apoptosis plays a role in the activation of NAFLD/NASH. Apoptotic hepatocytes stimulate immune cells and hepatic stellate cells toward the progression of fibrosis in the liver through the production of inflammasomes and cytokines. Abnormalities in glucose and lipid metabolism as well as microbiota accelerate these processes. The production of reactive oxygen species, oxidative stress, and endoplasmic reticulum stress is also involved. Cell death, including apoptosis, seems very important in the progression of NAFLD and NASH. Recently, inhibitors of apoptosis have been developed as drugs for the treatment of NASH and may prevent cirrhosis and HCC. Increased hepatocyte apoptosis may distinguish NASH from NAFLD, and the improvement of apoptosis could play a role in controlling the development of NASH. In this review, the association between apoptosis and NAFLD/NASH are discussed. This review could provide their knowledge, which plays a role in seeing the patients with NAFLD/NASH in daily clinical practice.

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Section: Discussionmentioning

confidence: 99%

Apoptosis and non-alcoholic fatty liver diseases

Kanda

Matsuoka

Yamazaki

et al. 2018

WJG

Self Cite

219

145

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“…It was reported that pre-treatment with IRE1α inhibitor reduced pro-inflammatory cytokines production in tumor necrosis factor (TNF)-receptor-associated periodic fever syndrome (TRAPS) dermal fibroblasts (DFs) ( Harrison et al, 2018 ). On the other hand, these inflammatory cytokines were also the downstream target genes of miR-122 ( Hsu et al, 2012 ; Nakamura et al, 2015 ; Yin et al, 2016 ; Tang et al, 2017 ). In the present study, the result showed that STF-083010 evidently inhibited the upregulation of hepatic α-SMA, Col1α1 and Col1α2 in mice, but these also may be attributed to HSCs expression and the fact that STF-083010 alleviates liver injury by inhibiting CCl 4 -mediated hepatocyte death.…”

Section: Discussionmentioning

confidence: 99%

Inositol-Requiring Enzyme 1 Alpha Endoribonuclease Specific Inhibitor STF-083010 Alleviates Carbon Tetrachloride Induced Liver Injury and Liver Fibrosis in Mice

et al. 2018

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Accumulating data demonstrated that hepatic endoplasmic reticulum (ER) stress was involved in the pathogenesis of liver fibrosis. Long-term chronic hepatocyte death contributed to liver fibrosis initiation and progression. Previous researches reported that ER stress sensor inositol-requiring enzyme 1 alpha (IRE1α) was first activated in the process of liver fibrosis. STF-083010 was an IRE1α RNase specific inhibitor. This study aimed to explore the effects of STF-083010 on carbon tetrachloride (CCl4)-induced liver injury and subsequent liver fibrosis. Mice were intraperitoneally (i.p.) injected with CCl4 (0.15 ml/kg) for 8 weeks. In STF-083010+CCl4 group, mice were injected with STF-083010 (30 mg/kg, i.p.), twice a week, beginning from the 6th week after CCl4 injection. CCl4 treatment markedly enhanced the levels of serum ALT, TBIL, DBIL and TBA, and STF-083010 had obviously extenuated CCl4-induced exaltation of ALT, DBIL, and TBA levels. CCl4-induced hepatic hydroxyproline and collagen I, major indicators of liver fibrosis, were alleviated by STF-083010. Additionally, CCl4-induced α-smooth muscle actin, a marker for hepatic stellate cells activation, was obviously attenuated in STF-083010-treated mice. Moreover, CCl4-induced upregulation of inflammatory cytokines was suppressed by STF-083010. Mechanistic exploration found that hepatic miR-122 was downregulated in CCl4-treated mice. Hepatic MCP1, CTGF, P4HA1, Col1α1, and Mmp9, target genes of miR-122, were upregulated in CCl4-treated mice. Interestingly, STF-083010 reversed CCl4-induced hepatic miR-122 downregulation. Correspondingly, STF-083010 inhibited CCl4-induced upregulation of miR-122 target genes. This study provides partial evidence that STF-083010 alleviated CCl4-induced liver injury and thus protected against liver fibrosis associated with hepatic miR-122.

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“…As some of these changes in NK‐cell markers showed similar changes on bulk CD8 + T cells and CD56 + NK T cells, the observed changes in the NK‐cell compartment might be the result of an overall decrease in immune activation upon a decline in HCV viral load. However, as miR‐122 has been implicated in immune regulation, direct effects of miR‐122 inhibition could also contribute to the changes in NK cells observed …”

Section: Discussionmentioning

confidence: 99%

“…However, as miR-122 has been implicated in immune regulation, direct effects of miR-122 inhibition could also contribute to the changes in NK cells observed. (25,26,32,33) Chronic CHC infection leads to dysfunctional ("exhausted") HCV-specific CD8 1 T cells. In patients successfully treated with IFN-free therapy, a restoration of the proliferative capacity of these HCV-specific CD8 1 T cells has been observed.…”

Section: Discussionmentioning

confidence: 99%

Immune phenotype and function of natural killer and T cells in chronic hepatitis C patients who received a single dose of anti‐MicroRNA‐122, RG‐101

et al. 2017

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MicroRNA-122 (miR-122) is an important host factor for the hepatitis C virus. Treatment with RG-101, a GalNAc conjugated anti-miR-122 oligonucleotide, resulted in a significant viral load reduction in patients with chronic hepatitis C (CHC) infection. Here, we analyzed the effects of RG-101 therapy on antiviral immunity. 32 CHC patients HCV genotype 1, 3 and 4 received a single subcutaneous administration with RG-101 at 2 mg/kg (n=14), 4 mg/kg (n=14) or placebo (n=2 per dosing group). Plasma and PBMCs were collected at multiple time points and comprehensive immunological analyses were performed. Following RG-101 administration, HCV RNA declined in all patients (mean decline at week 2: 3.27 log10 IU/mL). At week 8 HCV RNA was undetectable in 15/28 patients. Plasma IP-10 levels declined significantly upon dosing with RG-101. Furthermore, the frequency of NK cells increased, the proportion of NK cells expressing activating receptors normalized and NK cell IFN-γ production decreased after RG-101 dosing. By week 8 post RG-101 injection, functional HCV-specific IFN-γ-T cell responses declined significantly in patients who had undetectable HCV RNA. No increase in the magnitude of HCV-specific T cell responses was observed at later time points, including 3 patients who were HCV RNA negative 76 weeks post dosing. Conclusions Dosing with RG-101 is associated with a restoration of NK cell proportions and a decrease of NK cells expressing activation receptors. However, the magnitude and functionality of ex vivo HCV-specific T cell responses did not increase following RG-101 injection. Our data suggests that NK cells, but not HCV adaptive immunity may contribute to HCV viral control following RG-101 therapy.

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MicroRNA-122 Inhibits the Production of Inflammatory Cytokines by Targeting the PKR Activator PACT in Human Hepatic Stellate Cells

Cited by 37 publications

References 56 publications

Apoptosis and non-alcoholic fatty liver diseases

Apoptosis and non-alcoholic fatty liver diseases

Inositol-Requiring Enzyme 1 Alpha Endoribonuclease Specific Inhibitor STF-083010 Alleviates Carbon Tetrachloride Induced Liver Injury and Liver Fibrosis in Mice

Immune phenotype and function of natural killer and T cells in chronic hepatitis C patients who received a single dose of anti‐MicroRNA‐122, RG‐101

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