دورية أكاديمية
أعرض في EDS

NADPH Oxidase 1 in Liver Macrophages Promotes Inflammation and Tumor Development in Mice.

التفاصيل البيبلوغرافية
العنوان: NADPH Oxidase 1 in Liver Macrophages Promotes Inflammation and Tumor Development in Mice.
المؤلفون: Liang S; Department of Medicine, School of Medicine, University of California San Diego, La Jolla, California., Ma HY; Department of Medicine, School of Medicine, University of California San Diego, La Jolla, California., Zhong Z; Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, California., Dhar D; Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, California., Liu X; Department of Medicine, School of Medicine, University of California San Diego, La Jolla, California., Xu J; Department of Medicine, School of Medicine, University of California San Diego, La Jolla, California., Koyama Y; Department of Medicine, School of Medicine, University of California San Diego, La Jolla, California; Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Nishio T; Department of Medicine, School of Medicine, University of California San Diego, La Jolla, California; Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Karin D; Department of Medicine, School of Medicine, University of California San Diego, La Jolla, California., Karin G; Department of Medicine, School of Medicine, University of California San Diego, La Jolla, California., Mccubbin R; Department of Medicine, School of Medicine, University of California San Diego, La Jolla, California., Zhang C; Department of Medicine, School of Medicine, University of California San Diego, La Jolla, California; School of Public Health, Shandong University, Jinan, China., Hu R; Department of Medicine, School of Medicine, University of California San Diego, La Jolla, California; Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China., Yang G; Guangdong Pharmaceutical University, Guangzhou, China., Chen L; Department of Medicine, School of Medicine, University of California San Diego, La Jolla, California., Ganguly S; Department of Medicine, School of Medicine, University of California San Diego, La Jolla, California., Lan T; Guangdong Pharmaceutical University, Guangzhou, China., Karin M; Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, California., Kisseleva T; Department of Surgery, School of Medicine, University of California San Diego, La Jolla, California. Electronic address: tkisseleva@mail.ucsd.edu., Brenner DA; Department of Medicine, School of Medicine, University of California San Diego, La Jolla, California. Electronic address: dbrenner@ucsd.edu.
المصدر: Gastroenterology [Gastroenterology] 2019 Mar; Vol. 156 (4), pp. 1156-1172.e6. Date of Electronic Publication: 2018 Nov 13.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: W.B. Saunders Country of Publication: United States NLM ID: 0374630 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1528-0012 (Electronic) Linking ISSN: 00165085 NLM ISO Abbreviation: Gastroenterology Subsets: MEDLINE
أسماء مطبوعة: Publication: Philadelphia, PA : W.B. Saunders
Original Publication: Baltimore.
مواضيع طبية MeSH: Carcinoma, Hepatocellular/*genetics , Carcinoma, Hepatocellular/*pathology , Cell Transformation, Neoplastic/*genetics , Hepatitis/*genetics , Hepatocytes/*pathology , Liver Neoplasms, Experimental/*genetics , Liver Neoplasms, Experimental/*pathology , Macrophages/*enzymology , NADPH Oxidase 1/*genetics , NADPH Oxidase 4/*genetics, Alarmins/metabolism ; Animals ; Carcinoma, Hepatocellular/chemically induced ; Cell Proliferation/physiology ; Cells, Cultured ; Culture Media, Conditioned/pharmacology ; Diethylnitrosamine ; Enzyme Inhibitors/pharmacology ; Hepatic Stellate Cells ; Hepatocytes/physiology ; Humans ; Interleukin-6/metabolism ; Liver/metabolism ; Liver/pathology ; Liver Neoplasms, Experimental/chemically induced ; Macrophages/drug effects ; Macrophages/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; NADPH Oxidase 1/metabolism ; Necrosis ; STAT3 Transcription Factor/metabolism ; Tumor Burden ; Tumor Necrosis Factor-alpha/metabolism
مستخلص: Background & Aims: Although there are associations among oxidative stress, reduced nicotinamide adenine dinucleotide phosphate oxidase (NOX) activation, and hepatocellular carcinoma (HCC) development, it is not clear how NOX contributes to hepatocarcinogenesis. We studied the functions of different NOX proteins in mice after administration of a liver carcinogen.
Methods: Fourteen-day-old Nox1 -/- mice, Nox4 -/- mice, Nox1 -/- Nox4 -/- (double-knockout) mice, and wild-type (WT) C57BL/6 mice were given a single intraperitoneal injection of diethylnitrosamine (DEN) and liver tumors were examined at 9 months. We also studied the effects of DEN in mice with disruption of Nox1 specifically in hepatocytes (Nox1 ΔHep ), hepatic stellate cells (Nox1 ΔHep ), or macrophages (Nox1 ΔMac ). Some mice were also given injections of the NOX1-specific inhibitor ML171. To study the acute effects of DEN, 8-12-week-old mice were given a single intraperitoneal injection, and liver and serum were collected at 72 hours. Liver tissues were analyzed by histologic examination, quantitative polymerase chain reaction, and immunoblots. Hepatocytes and macrophages were isolated from WT and knockout mice and analyzed by immunoblots.
Results: Nox4 -/- mice and WT mice developed liver tumors within 9 months after administration of DEN, whereas Nox1 -/- mice developed 80% fewer tumors, which were 50% smaller than those of WT mice. Nox1 ΔHep and Nox1 ΔHSC mice developed liver tumors of the same number and size as WT mice, whereas Nox1 ΔMac developed fewer and smaller tumors, similar to Nox1 -/- mice. After DEN injection, levels of tumor necrosis factor, interleukin 6 (IL6), and phosphorylated signal transducer and activator of transcription 3 were increased in livers from WT, but not Nox1 -/- or Nox1 ΔMac , mice. Conditioned medium from necrotic hepatocytes induced expression of NOX1 in cultured macrophages, followed by expression of tumor necrosis factor, IL6, and other inflammatory cytokines; this medium did not induce expression of IL6 or cytokines in Nox1 ΔMac macrophages. WT mice given DEN followed by ML171 developed fewer and smaller liver tumors than mice given DEN followed by vehicle.
Conclusions: In mice given injections of a liver carcinogen (DEN), expression of NOX1 by macrophages promotes hepatic tumorigenesis by inducing the production of inflammatory cytokines. We propose that upon liver injury, damage-associated molecular patterns released from dying hepatocytes activate liver macrophages to produce cytokines that promote tumor development. Strategies to block NOX1 or these cytokines might be developed to slow hepatocellular carcinoma progression.
(Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)
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معلومات مُعتمدة: R37 AI043477 United States AI NIAID NIH HHS; P42 ES010337 United States ES NIEHS NIH HHS; R01 CA211794 United States CA NCI NIH HHS; R01 DK111866 United States DK NIDDK NIH HHS; R01 DK099205 United States DK NIDDK NIH HHS; U01 AA022614 United States AA NIAAA NIH HHS; P50 AA011999 United States AA NIAAA NIH HHS; R01 AI043477 United States AI NIAID NIH HHS; R01 DK101737 United States DK NIDDK NIH HHS; R01 CA198103 United States CA NCI NIH HHS
فهرسة مساهمة: Keywords: Hepatocellular carcinoma; Inflammation; Macrophage; Reactive oxygen species
المشرفين على المادة: 0 (Alarmins)
0 (Culture Media, Conditioned)
0 (Enzyme Inhibitors)
0 (Interleukin-6)
0 (STAT3 Transcription Factor)
0 (Stat3 protein, mouse)
0 (Tumor Necrosis Factor-alpha)
0 (interleukin-6, mouse)
3IQ78TTX1A (Diethylnitrosamine)
EC 1.6.3.- (NADPH Oxidase 1)
EC 1.6.3.- (NADPH Oxidase 4)
EC 1.6.3.- (NOX1 protein, human)
EC 1.6.3.- (NOX1 protein, mouse)
EC 1.6.3.- (Nox4 protein, mouse)
تواريخ الأحداث: Date Created: 20181117 Date Completed: 20190403 Latest Revision: 20200309
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC6409207
DOI: 10.1053/j.gastro.2018.11.019
PMID: 30445007
قاعدة البيانات: MEDLINE
الوصف
تدمد:1528-0012
DOI:10.1053/j.gastro.2018.11.019