title: Interleukin-1 Receptor Antagonist Has a Novel Function in the Regulation of Matrix Metalloproteinase-13 Expression.
abstract: Interleukin-1 receptor antagonist (IL-1Ra) is an IL-1 family member, which binds to IL-1 receptors but does not induce any intracellular signaling. We addressed whether IL-1Ra has a novel function in regulation of the extracellular matrix or adhesion molecules. Polymerase chain reaction array analysis demonstrated a ~5-fold increase in matrix metalloproteinase 13 (MMP-13) mRNA expression of IL-1Ra siRNA-transfected Ca9-22 human oral squamous epithelial carcinoma cells compared with the control. In fact, MMP-13 mRNA and protein expression as well as its activity in IL-1Ra siRNA-transfected Ca9-22 cell lines were significantly higher than those in the control. IL-1Ra siRNA treatment resulted in strong elevation of MMP-13 expression, whereas addition of rhIL-1Ra (40 ng/ml) suppressed MMP-13 expression, suggesting that IL-1Ra had a specific effect on MMP-13 induction. IL-1Ra siRNA could potently suppress IL-1α. No significant difference was found between the MMP-13 mRNA expression of IL-1Ra siRNA-transfected cells and those treated with anti-IL-1α or anti-IL-1β antibodies. These results suggested that continuous supply of IL-1 had no effect on the induction of MMP-13 by IL-1Ra siRNA. Histopathological investigation of MMP-13 in periodontal tissue showed specific localization in the junctional epithelial cells of IL-1Ra knockout (KO) mice. Furthermore, infection with Aggregatibacter actinomycetemcomitans to establish an experimental periodontitis model resulted in predominant localization of MMP-13 along apical junctional epithelial cells. Laminin-5, which is degraded by MMP-13, was found in the internal basal lamina of wild-type mice, whereas the internal basal lamina of IL-1Ra KO mice did not show obvious laminin-5 localization. In particular, laminin-5 localization almost disappeared in the internal basal lamina of IL-1Ra KO mice infected with A. actinomycetemcomitans, suggesting that the suppression of IL-1Ra resulted in strong induction of MMP-13 that degraded laminin-5. In conclusion, IL-1Ra is associated with MMP-13 expression and has a novel function in such regulation without interference of the IL-1 signaling cascade.
authors.affiliation: Department of Periodontology, School of Dentistry, Aichi Gakuin University, Chikusa-ku, Nagoya, Aichi, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Goto
authors.affiliation: Department of Operative Dentistry, Endodontology, and Periodontology, School of Dentistry, Matsumoto Dental University, Nagano, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ishihara
authors.affiliation: Department of Periodontology, School of Dentistry, Aichi Gakuin University, Chikusa-ku, Nagoya, Aichi, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kikuchi
authors.affiliation: Department of Periodontology, School of Dentistry, Aichi Gakuin University, Chikusa-ku, Nagoya, Aichi, Japan.
authors.forename: Ario
authors.initials: A
authors.lastname: Izawa
authors.affiliation: Department of Endodontics, School of Dentistry, Aichi Gakuin University, Chikusa-ku, Nagoya, Aichi, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Ozeki
authors.affiliation: Department of Periodontology, School of Dentistry, Aichi Gakuin University, Chikusa-ku, Nagoya, Aichi, Japan.
authors.forename: Eijiro
authors.initials: E
authors.lastname: Okabe
authors.affiliation: Department of Periodontology, School of Dentistry, Aichi Gakuin University, Chikusa-ku, Nagoya, Aichi, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kamiya
authors.affiliation: Department of Periodontology, School of Dentistry, Aichi Gakuin University, Chikusa-ku, Nagoya, Aichi, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ozawa
authors.affiliation: Department of Periodontology, School of Dentistry, Aichi Gakuin University, Chikusa-ku, Nagoya, Aichi, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Mizutani
authors.affiliation: Department of Periodontology, School of Dentistry, Aichi Gakuin University, Chikusa-ku, Nagoya, Aichi, Japan.
authors.forename: Genta
authors.initials: G
authors.lastname: Yamamoto
authors.affiliation: Department of Medicinal Biochemistry, School of Pharmacy, Aichi Gakuin University, Chikusa-ku, Nagoya, Japan.
authors.forename: Makio
authors.initials: M
authors.lastname: Mogi
authors.affiliation: Department of Endodontics, School of Dentistry, Aichi Gakuin University, Chikusa-ku, Nagoya, Aichi, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakata
authors.affiliation: Department of Pathology, School of Dentistry, Aichi Gakuin University, Chikusa-ku, Nagoya, Japan.
authors.forename: Hatsuhiko
authors.initials: H
authors.lastname: Maeda
authors.affiliation: Department of Periodontology, School of Dentistry, Aichi Gakuin University, Chikusa-ku, Nagoya, Aichi, Japan.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Noguchi
authors.affiliation: Department of Periodontology, School of Dentistry, Aichi Gakuin University, Chikusa-ku, Nagoya, Aichi, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Mitani
mesh_terms: D016976:Aggregatibacter actinomycetemcomitans; D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics / Q000378:metabolism*; D053582:Interleukin-1alpha / Q000096:biosynthesis / Q000235:genetics; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D016871:Pasteurellaceae Infections / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D000097794:Kalinin
chemical_list: D015815:Cell Adhesion Molecules; D053590:Interleukin 1 Receptor Antagonist Protein; D053582:Interleukin-1alpha; D053509:Matrix Metalloproteinase 13; D034741:RNA, Small Interfering; D000097794:Kalinin; C508584:IL1A protein, human; C507763:IL1RN protein, human; C507079:MMP13 protein, human; C507081:Mmp13 protein, mouse