Interleukin-1 Receptor Antagonist Has a Novel Function in the Regulation of Matrix Metalloproteinase-13 Expression

Hisashi Goto; Yuichi Ishihara; Takeshi Kikuchi; Ario Izawa; Nobuaki Ozeki; Eijiro Okabe; Yosuke Kamiya; Yusuke Ozawa; Hiroki Mizutani; Genta Yamamoto; Makio Mogi; Kazuhiko Nakata; Hatsuhiko Maeda; Toshihide Noguchi; Akio Mitani

doi:10.1371/journal.pone.0140942

Interleukin-1 Receptor Antagonist Has a Novel Function in the Regulation of Matrix Metalloproteinase-13 Expression

PLoS One. 2015 Oct 16;10(10):e0140942. doi: 10.1371/journal.pone.0140942. eCollection 2015.

Authors

Affiliations

¹ Department of Periodontology, School of Dentistry, Aichi Gakuin University, Chikusa-ku, Nagoya, Aichi, Japan.
² Department of Operative Dentistry, Endodontology, and Periodontology, School of Dentistry, Matsumoto Dental University, Nagano, Japan.
³ Department of Endodontics, School of Dentistry, Aichi Gakuin University, Chikusa-ku, Nagoya, Aichi, Japan.
⁴ Department of Medicinal Biochemistry, School of Pharmacy, Aichi Gakuin University, Chikusa-ku, Nagoya, Japan.
⁵ Department of Pathology, School of Dentistry, Aichi Gakuin University, Chikusa-ku, Nagoya, Japan.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aggregatibacter actinomycetemcomitans
Animals
Cell Adhesion Molecules / genetics
Cell Adhesion Molecules / metabolism
Cell Line, Tumor
Gene Expression Regulation, Enzymologic / physiology*
Humans
Interleukin 1 Receptor Antagonist Protein / genetics
Interleukin 1 Receptor Antagonist Protein / metabolism*
Interleukin-1alpha / biosynthesis
Interleukin-1alpha / genetics
Kalinin
Matrix Metalloproteinase 13 / biosynthesis*
Matrix Metalloproteinase 13 / genetics
Mice
Mice, Knockout
Pasteurellaceae Infections / genetics
Pasteurellaceae Infections / metabolism
Proteolysis*
RNA, Small Interfering / genetics
Signal Transduction / physiology*

Substances

Cell Adhesion Molecules
IL1A protein, human
IL1RN protein, human
Interleukin 1 Receptor Antagonist Protein
Interleukin-1alpha
RNA, Small Interfering
MMP13 protein, human
Matrix Metalloproteinase 13
Mmp13 protein, mouse

Grants and funding

This work was supported by the Japan Society for the Promotion of Science KAKENHI (grant number: 24593137, 15K11402), http://www.jsps.go.jp. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.