title: ISG54 and ISG56 are induced by TLR3 signaling in U373MG human astrocytoma cells: possible involvement in CXCL10 expression.
abstract: Toll-like receptor (TLR) 3 is a pattern recognition receptor that recognizes double-stranded RNA (dsRNA). TLR3 signaling in astrocytes leads to the expression of interferon-β (IFN-β), and IFN-β regulates immune and inflammatory reactions by inducing IFN-stimulated genes (ISGs). We demonstrated in the present study that polyinosinic-polycytidylic acid (poly IC), an authentic dsRNA, up-regulated the expression of ISG54 and ISG56 in U373MG human astrocytoma cells. This reaction was confirmed to be mediated via the TLR3/IFN-β pathway. We also found that ISG56 positively regulates the expression of ISG54, retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). In addition, positive feedback loops were found between ISG54 and ISG56, and also between ISG54 and RIG-I. RNA interference experiments revealed that all of ISG54, ISG56, RIG-I and MDA5 were involved in the poly IC-induced expression of a chemokine CXCL10. These results suggest that ISG54 and ISG56 are involved in the induction of CXCL10 in TLR3/IFN-β signaling at least partly by co-operating with RIG-I and MDA5. ISG54 and ISG56 may contribute to immune and inflammatory reactions elicited by the TLR3/IFN-β signaling pathway in astrocytes, and may play an important role both in antiviral immunity and in neuroinflammatory diseases.
authors.affiliation: Department of Vascular Biology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan. Electronic address: timaizum@cc.hirosaki-u.ac.jp.
authors.forename: Tadaatsu
authors.initials: T
authors.lastname: Imaizumi
authors.affiliation: Department of Vascular Biology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Numata
authors.affiliation: Department of Vascular Biology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan.
authors.forename: Chikashi
authors.initials: C
authors.lastname: Yano
authors.affiliation: Department of Vascular Biology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan.
authors.forename: Hidemi
authors.initials: H
authors.lastname: Yoshida
authors.affiliation: Department of Vascular Biology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Meng
authors.affiliation: Department of Vascular Biology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Hayakari
authors.affiliation: Department of Vascular Biology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan.
authors.forename: Fei
authors.initials: F
authors.lastname: Xing
authors.affiliation: Department of Vascular Biology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan.
authors.forename: Lian
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Vascular Biology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan.
authors.forename: Tomoh
authors.initials: T
authors.lastname: Matsumiya
authors.affiliation: Department of Neuropathology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan.
authors.forename: Kunikazu
authors.initials: K
authors.lastname: Tanji
authors.affiliation: Department of Gastroenterology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tatsuta
authors.affiliation: Department of Pharmacology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Murakami
authors.affiliation: Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan; Department of School Health Science, Faculty of Education, Hirosaki University, Hirosaki 036-8560, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tanaka
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D045744:Cell Line, Tumor; D054357:Chemokine CXCL10 / Q000378:metabolism*; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007369:Interferon Inducers / Q000494:pharmacology; D000072640:Interferon-Induced Helicase, IFIH1; D018302:Neoplasms, Neuroepithelial / Q000473:pathology; D011070:Poly I-C / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D016601:RNA-Binding Proteins; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; C484290:IFIT1 protein, human; C484289:IFIT2 protein, human; D007369:Interferon Inducers; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D014157:Transcription Factors; C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1; D011070:Poly I-C
keywords: CXCL10; IFN-β; ISG54; ISG56; TLR3; U373MG cells