title: MDA5 and ISG56 mediate CXCL10 expression induced by toll-like receptor 4 activation in U373MG human astrocytoma cells.
abstract: Toll-like receptor (TLR) 4 is a pattern recognition receptor, and recognizes not only bacterial lipopolysaccharide (LPS) but also endogenous danger-associated molecular patterns released from dying or injured cells. It has been reported that TLR4 signaling in astrocytes plays an important role in various neurological diseases. However, details of TLR4 signaling in astrocytes are not fully elucidated. In the present study, we demonstrated that TLR4 signaling, induced by LPS, increases the expression of melanoma differentiation-associated gene 5 (MDA5) and interferon (IFN)-stimulated gene 56 (ISG56) in U373MG human astrocytoma cells. We also found that nuclear factor-κB, p38 mitogen-activated protein kinase and IFN-β are involved in the expression of MDA5 and ISG56 induced by LPS. RNA interference experiments revealed that MDA5 and ISG56 positively regulate the LPS-induced expression of a chemokine CXCL10, but not CCL2. In addition, it was suggested that MDA5 and ISG56 constitute a positive feedback loop. These results suggest that MDA5 and ISG56 may contribute not only to physiological inflammatory reactions but also to the pathogenesis of various neurological diseases elicited by TLR4 in astrocytes, at least in part, by regulating the expression of CXCL10.
authors.affiliation: Department of Vascular Biology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan. timaizum@cc.hirosaki-u.ac.jp
authors.forename: Tadaatsu
authors.initials: T
authors.lastname: Imaizumi
authors.forename: Keishu
authors.initials: K
authors.lastname: Murakami
authors.forename: Kasumi
authors.initials: K
authors.lastname: Ohta
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Seki
authors.forename: Tomoh
authors.initials: T
authors.lastname: Matsumiya
authors.forename: Pengfei
authors.initials: P
authors.lastname: Meng
authors.forename: Ryo
authors.initials: R
authors.lastname: Hayakari
authors.forename: Fei
authors.initials: F
authors.lastname: Xing
authors.forename: Tomomi
authors.initials: T
authors.lastname: Aizawa-Yashiro
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tatsuta
authors.forename: Hidemi
authors.initials: H
authors.lastname: Yoshida
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kijima
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D001253:Astrocytes / Q000276:immunology / Q000378:metabolism; D001254:Astrocytoma / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000378:metabolism*; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D006801:Humans; D000072640:Interferon-Induced Helicase, IFIH1; D008070:Lipopolysaccharides / Q000276:immunology; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D016601:RNA-Binding Proteins; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; C484290:IFIT1 protein, human; D008070:Lipopolysaccharides; D016328:NF-kappa B; D016601:RNA-Binding Proteins; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014157:Transcription Factors; D048051:p38 Mitogen-Activated Protein Kinases; C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1
keywords: Astrocytes; CXCL10; DAMPs; IFN; ISG56; LPS; MAPK; MDA5; NF-κB; PAMPs; PRRs; RIG-I; TLR; TLR4; Toll-like receptor; U373MG cells; danger-associated molecular patterns; interferon; interferon-stimulated gene 56; lipopolysaccharide; melanoma differentiation-associated gene 5; mitogen-activated protein kinase; nuclear factor-κB; pathogen-associated molecular patterns; pattern recognition receptors; retinoic acid-inducible gene-I