Post-Transcriptional Regulation of Toll-Interacting Protein in the Intestinal Epithelium

Sugi, Yutaka; Takahashi, Kyôko; Kurihara, Kenta; Nakata, Kazuaki; Narabayashi, Hikari; Hamamoto, Yüji; Suzuki, Makoto; Tsuda, Masato; Hanazawa, Shigemasa; Hosono, Akira; Kaminogawa, Shuichi

doi:10.1371/journal.pone.0164858

Cited by 12 publications

(12 citation statements)

References 69 publications

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“…Tollip expression can be regulated at the transcriptional 27 , as well as post-transcriptional level 11 . The 3′UTR of Tollip contains a miR31 binding site; miR31 binding inhibits translation 11 . Here, using TargetScan, we identified a miR291b binding site in the Tollip 3′UTR that was associated with decreased Tollip protein quantity in Kupffer cells.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, Tollip, a negative regulator of TLR4-MyD88-IRAK signaling 9 , 10 , was identified as a target of miR291b. Tollip is known to be post-transcriptionally regulated by other miRNAs, including miR-31 11 . Tollip suppresses the sensitivity of macrophages to stimulation by LPS, as well as IL1-β 9 , although this response may vary with dose of LPS 12 , 13 ; Tollip expression was decreased in Kupffer cells after chronic ethanol, but restored by HA35; restoration of Tollip expression contributed to the normalization of TLR4 signaling in Kupffer cells after chronic ethanol feeding.…”

Section: Introductionmentioning

confidence: 99%

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Hyaluronic acid 35 normalizes TLR4 signaling in Kupffer cells from ethanol-fed rats via regulation of microRNA291b and its target Tollip

Saikia

Roychowdhury

Bellos

et al. 2017

Sci Rep

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TLR4 signaling in hepatic macrophages is increased after chronic ethanol feeding. Treatment of hepatic macrophages after chronic ethanol feeding with small-specific sized hyaluronic acid 35 (HA35) normalizes TLR4 signaling; however, the mechanisms for HA35 action are not completely understood. Here we used Next Generation Sequencing of microRNAs to identify negative regulators of TLR4 signaling reciprocally modulated by ethanol and HA35 in hepatic macrophages. Eleven microRNAs were up-regulated by ethanol; only 4 microRNAs, including miR291b, were decreased by HA35. Bioinformatics analysis identified Tollip, a negative regulator of TLR4, as a target of miR291b. Tollip expression was decreased in hepatic macrophages from ethanol-fed rats, but treatment with HA35 or transfection with a miR291b hairpin inhibitor restored Tollip expression and normalized TLR4-stimulated TNFα expression. In peripheral blood monocytes isolated from patients with alcoholic hepatitis, expression of TNFα mRNA was robustly increased in response to challenge with lipopolysaccharide. Importantly, pre-treatment with HA35 reduced TNFα expression by more than 50%. Taken together, we have identified miR291b as a critical miRNA up-regulated by ethanol. Normalization of the miR291b → Tollip pathway by HA35 ameliorated ethanol-induced sensitization of TLR4 signaling in macrophages/monocytes, suggesting that HA35 may be a novel therapeutic agent in the treatment of ALD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hyaluronic acid 35 normalizes TLR4 signaling in Kupffer cells from ethanol-fed rats via regulation of microRNA291b and its target Tollip

Saikia

Roychowdhury

Bellos

et al. 2017

Sci Rep

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“…Small IECs (SIECs) and CoECs were prepared from the whole small intestine and the whole colon of mice, respectively. Epithelial cell preparation was performed as described previously (25). After removing Peyer patches, the tissues were cut into 2-3-mm pieces and washed in HBSS supplemented with 1 mM DTT and 0.5 mM EDTA accompanied by shaking.…”

Section: Iec Preparationmentioning

confidence: 99%

Regulation of Gene Expression through Gut Microbiota-Dependent DNA Methylation in Colonic Epithelial Cells

et al. 2020

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A huge number of commensal bacteria inhabit the intestine, which is equipped with the largest immune system in the body. Recently, the regulation of various physiological functions of the host by these bacteria has attracted attention. In this study, the effects of commensal bacteria on gene expression in colonic epithelial cells (CoECs) were investigated with focus on regulation of DNA methylation. RNA sequencing analyses of CoECs from conventional, germ-free, and MyD88 2/2 mice indicated that, out of the genes affected by commensal bacteria, those downregulated in a MyD88-independent manner were most frequently observed. Furthermore, when the 59 regions of genes downregulated by commensal bacteria in CoECs were captured using a customized array and immunoprecipitated with the anti-methyl cytosine Ab, a certain population of these genes was found to be highly methylated. Comprehensive analysis of DNA methylation in the 59 regions of genes in CoECs from conventional and germ-free mice upon pulldown assay with methyl-CpG-binding domain protein 2 directly demonstrated that DNA methylation in these regions was influenced by commensal bacteria. Actually, commensal bacteria were shown to control expression of Aldh1a1, which encodes a retinoic acid-producing enzyme and plays an important role in the maintenance of intestinal homeostasis via DNA methylation in the overlapping 59 region of Tmem267 and 3110070M22Rik genes in CoECs. Collectively, it can be concluded that regulation of DNA methylation in the 59 regions of a specific population of genes in CoECs acts as a mechanism by which commensal bacteria have physiological effects on the host.

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“…The protocols for reverse transcription and quantitative analysis of mRNA or miRNA expression by qPCR were described in a previous report (32). We normalized mRNA expression to that of GAPDH.…”

Section: Quantitative Rt-pcr (Qrt-pcr)mentioning

confidence: 99%

“…Cell lysates were prepared as described previously (32). We used primary antibodies against ARF4 (Proteintech), claudin-4 (Santa Cruz Biotechnology, Dallas, TX), occludin (Abcam, Cambridge, UK), and ␤-actin (Abcam).…”

Section: Western Blottingmentioning

confidence: 99%

Commensal microbiota-induced microRNA modulates intestinal epithelial permeability through the small GTPase ARF4

Nakata

Sugi

Narabayashi

et al. 2017

Journal of Biological Chemistry

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The intestinal tract contains many commensal bacteria that modulate various physiological host functions. Dysbiosis of commensal bacteria triggers dysfunction of the intestinal epithelial barrier, leading to the induction or aggravation of intestinal inflammation. To elucidate whether microRNA plays a role in commensal microbiome-dependent intestinal epithelial barrier regulation, we compared transcripts in intestinal epithelial cells (IECs) from conventional and germ-free mice and found that commensal bacteria induced the expression of miR-21-5p in IECs. miR-21-5p increased intestinal epithelial permeability and up-regulated ADP ribosylation factor 4 (ARF4), a small GTPase, in the IEC line Caco-2. We also found that ARF4 expression was up-regulated upon suppression of phosphatase and tensin homolog () and programmed cell death 4 (), which are known miR-21-5p targets, by RNAi. Furthermore, ARF4 expression in epithelial cells of the large intestine was higher in conventional mice than in germ-free mice. ARF4 suppression in the IEC line increased the expression of tight junction proteins and decreased intestinal epithelial permeability. These results indicate that commensal microbiome-dependent miR-21-5p expression in IECs regulates intestinal epithelial permeability via ARF4, which may therefore represent a target for preventing or managing dysfunction of the intestinal epithelial barrier.

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Post-Transcriptional Regulation of Toll-Interacting Protein in the Intestinal Epithelium

Cited by 12 publications

References 69 publications

Hyaluronic acid 35 normalizes TLR4 signaling in Kupffer cells from ethanol-fed rats via regulation of microRNA291b and its target Tollip

Hyaluronic acid 35 normalizes TLR4 signaling in Kupffer cells from ethanol-fed rats via regulation of microRNA291b and its target Tollip

Regulation of Gene Expression through Gut Microbiota-Dependent DNA Methylation in Colonic Epithelial Cells

Commensal microbiota-induced microRNA modulates intestinal epithelial permeability through the small GTPase ARF4

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