title: Induction of the Matrix Metalloproteinase 13 Gene in Bronchial Epithelial Cells by Interferon and Identification of its Novel Functional Polymorphism.
abstract: Matrix metalloproteinases (MMPs) are a class of extra-cellular and membrane-bound proteases involved in a wide array of physiological and pathological processes including tissue remodeling, inflammation, and cytokine secretion and activation. MMP-13 has been shown to be involved in lung diseases such as acute lung injury, viral infections, and chronic obstructive pulmonary disease; however, the molecular pathogenesis of MMP-13 in these conditions is not well understood. In this study, we investigated the mechanisms and roles of MMP-13 secretion in human small airway epithelial cells (SAECs) and functional polymorphisms of the MMP13 gene. Polyinosinic-polycytidylic acid (poly(I:C)) and interferon β (IFN-β) stimulated the secretion of MMP-13 from SAECs by more than several hundred-fold. Stimulation of the secretion by poly(I:C) was abolished by SB304680 (p38 inhibitor), LY294002 (PI3K inhibitor), Janus kinase (JAK) inhibitor I, RNA-activated protein kinase (PKR) inhibitor, and Bay 11-7082 (NF-κB inhibitor), while stimulation by IFN-β was inhibited by all except Bay 11-7082. These data suggested that the secretion of MMP-13 was mediated through IFN receptor pathways independently of nuclear factor kappa B (NF-κB) and that poly(I:C) stimulated IFN secretion in an NF-κB-dependent manner from SAECs, leading to IFN-stimulated MMP-13 secretion. Chemical MMP-13 inhibitors and MMP-13 small interfering RNA (siRNA) inhibited IFN-stimulated secretion of interferon gamma-inducible protein 10 (IP-10) and regulated on activation, normal T-cell expressed and secreted (RANTES), suggesting that MMP-13 is involved in the secretion of these virus-induced proinflammatory chemokines. We identified a novel functional polymorphism in the promoter region of the MMP13 gene. The MMP13 gene may play important roles in defense mechanisms of airway epithelial cells.
authors.affiliation: Department of Public Health, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Mashimo
authors.affiliation: Department of Education and Training, Tohoku Medical Megabank Organization, Tohoku University, 2-1 Seiryomachi, Aobaku, Sendai, 980-8573, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Sakurai-Yageta
authors.affiliation: The Department of Pediatrics, Toho University School of Medicine, Tokyo, Japan.
authors.forename: Misa
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Takayasu
authors.initials: T
authors.lastname: Arima
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Morita
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Yuzaburo
authors.initials: Y
authors.lastname: Inoue
authors.affiliation: Department of Pediatrics, National Shimoshizu Hospital, Yotsukaido, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Sato
authors.affiliation: Department of Pediatrics, National Shimoshizu Hospital, Yotsukaido, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Nishimuta
authors.affiliation: Department of Pediatrics, National Shimoshizu Hospital, Yotsukaido, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Department of Pediatrics, National Shimoshizu Hospital, Yotsukaido, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Department of Allergy and Rheumatology, Chiba Children's Hospital, Chiba, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Hoshioka
authors.affiliation: Department of Allergy and Rheumatology, Chiba Children's Hospital, Chiba, Japan.
authors.forename: Minako
authors.initials: M
authors.lastname: Tomiita
authors.affiliation: Department of Allergy and Rheumatology, Chiba Children's Hospital, Chiba, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Yamaide
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Kohno
authors.affiliation: Department of Otorhinolaryngology and Head and Neck Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Okamoto
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Shimojo
authors.affiliation: Department of Public Health, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Hata
authors.affiliation: Department of Public Health, Graduate School of Medicine, Chiba University, Chiba, Japan. ysuzuki@megabank.tohoku.ac.jp.|Department of Education and Training, Tohoku Medical Megabank Organization, Tohoku University, 2-1 Seiryomachi, Aobaku, Sendai, 980-8573, Japan. ysuzuki@megabank.tohoku.ac.jp.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Suzuki
mesh_terms: D001980:Bronchi / Q000166:cytology* / Q000473:pathology; D002478:Cells, Cultured; D018925:Chemokines; D004847:Epithelial Cells / Q000166:cytology / Q000201:enzymology*; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology; D007372:Interferons / Q000494:pharmacology / Q000502:physiology*; D053509:Matrix Metalloproteinase 13 / Q000235:genetics* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation
chemical_list: D018925:Chemokines; D016328:NF-kappa B; D016899:Interferon-beta; D007372:Interferons; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D011070:Poly I-C
keywords: airway epithelial cell; collagenase 3; gene expression; infection; interferron beta; matrix metalloproteinase 13; polymorphism