Potential Relevance of Cytoplasmic Viral Sensors and Related Regulators Involving Innate Immunity in Antiviral Response

Yasuhiro Asahina; Namiki Izumi; Itsuko Hirayama; Tomohiro Tanaka; Mitsuaki Sato; Yutaka Yasui; Nobutoshi Komatsu; Naoki Umeda; Takanori Hosokawa; Ken Ueda; Kaoru Tsuchiya; Hiroyuki Nakanishi; Jun Itakura; Masayuki Kurosaki; Nobuyuki Enomoto; Megumi Tasaka; Naoya Sakamoto; Shozo Miyake

doi:10.1053/j.gastro.2008.02.019

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Potential Relevance of Cytoplasmic Viral Sensors and Related Regulators Involving Innate Immunity in Antiviral Response

Journal article

Peer reviewed

Potential Relevance of Cytoplasmic Viral Sensors and Related Regulators Involving Innate Immunity in Antiviral Response

Yasuhiro Asahina, Namiki Izumi, Itsuko Hirayama, Tomohiro Tanaka, Mitsuaki Sato, Yutaka Yasui, Nobutoshi Komatsu, Naoki Umeda, Takanori Hosokawa, Ken Ueda, …

Gastroenterology (New York, N.Y. 1943), Vol.134(5), pp.1396-1405

2008

DOI: 10.1053/j.gastro.2008.02.019

PMID: 18471516

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Abstract

Background & Aims: Clinical significance of molecules involving innate immunity in treatment response remains unclear. The aim is to elucidate the mechanisms underlying resistance to antiviral therapy and predictive usefulness of gene quantification in chronic hepatitis C (CH-C). Methods: We conducted a human study in 74 CH-C patients treated with pegylated interferon α-2b and ribavirin and 5 nonviral control patients. Expression of viral sensors, adaptor molecule, related ubiquitin E3-ligase, and modulators were quantified. Results: Hepatic RIG-I, MDA5, LGP2, ISG15, and USP18 in CH-C patients were up-regulated at 2- to 8-fold compared with nonhepatitis C virus patients with a relatively constitutive Cardif. Hepatic RIG-I, MDA5, and LGP2 were significantly up-regulated in nonvirologic responders (NVR) compared with transient (TR) or sustained virologic responders (SVR). Cardif and RNF125 were negatively correlated with RIG-I and significantly suppressed in NVR. Differences among clinical responses in RIG-I/Cardif and RIG-I/RNF125 ratios were conspicuous (NVR/TR/SVR = 1.3:0.6:0.4 and 2.3:1.3:0.8, respectively). Like viral sensors, ISG15 and USP18 were significantly up-regulated in NVR (4-fold and 2.3-fold, respectively). Multivariate and receiver operator characteristic analyses revealed higher RIG-I/Cardif ratio, ISG15, and USP18 predicted NVR. Lower Cardif in NVR was confirmed by its protein level in Western blot. Also, transcriptional responses in peripheral blood mononuclear cells to the therapy were rapid and strong except for Cardif in not only a positive (RIG-I, ISG15, and USP18) but also in a negative regulatory manner (RNF125). Conclusions: NVR may have adopted a different equilibrium in their innate immune response. High RIG-I/Cardif and RIG-I/RNF125 ratios and ISG15 and USP18 are useful in identifying NVR.

ROC

G3PDH

RIG-I

VISA

ISG15

NVR

Cardif

PBMC

USP18

SVR

CARD

MDA5

UBP43

MAVS

RNF125

PEG-IFN

HCV

IPS-1

Details

Title: Subtitle: Potential Relevance of Cytoplasmic Viral Sensors and Related Regulators Involving Innate Immunity in Antiviral Response
Creators: Yasuhiro Asahina - Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
Namiki Izumi - Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
Itsuko Hirayama - Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
Tomohiro Tanaka - Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
Mitsuaki Sato - Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
Yutaka Yasui - Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
Nobutoshi Komatsu - Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
Naoki Umeda - Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
Takanori Hosokawa - Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
Ken Ueda - Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
Kaoru Tsuchiya - Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
Hiroyuki Nakanishi - Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
Jun Itakura - Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
Masayuki Kurosaki - Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
Nobuyuki Enomoto - First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
Megumi Tasaka - Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
Naoya Sakamoto - Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
Shozo Miyake - Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
Resource Type: Journal article
Publication Details: Gastroenterology (New York, N.Y. 1943), Vol.134(5), pp.1396-1405
DOI: 10.1053/j.gastro.2008.02.019
PMID: 18471516
NLM abbreviation: Gastroenterology
ISSN: 0016-5085
eISSN: 1528-0012
Publisher: Elsevier Inc
Grant note: DOI: 10.13039/501100007669, name: Miyakawa Memorial Research Foundation; DOI: 10.13039/501100001700, name: Ministry of Education, Culture, Sports, Science and Technology; DOI: 10.13039/501100003478, name: Ministry of Health, Labour and Welfare
Language: English
Date published: 2008
Academic Unit: Gastroenterology and Hepatology; Internal Medicine
Record Identifier: 9984094354002771

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