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

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

doi:10.1371/journal.pone.0140942

Hisashi Goto, Nobuaki Ozeki + Show 14 more

Open Access

https://doi.org/10.1371/journal.pone.0140942

Copy DOI

Journal: PloS one	Publication Date: Oct 16, 2015
Citations: 13	License type: CC BY 4.0

Affiliation: Aichi Gakuin University, Matsumoto Dental University

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.

Highlights

Interleukin (IL)-1 is closely associated with inflammatory tissue destruction in rheumatoid arthritis and periodontitis [1, 2]
Studies have already shown that tissue inhibitor of metalloproteinase (TIMP)-2 is induced by cytokines, TIMP-1 and TIMP-2 expression levels were unchanged in IL-1 receptor antagonist (IL-1Ra) small interfering RNA (siRNA)-transfected cells compared with the control
By investigating the effect of IL-1Ra on the junctional epithelium that attaches to the enamel surface via hemidesmosomes in which laminin-5 and integrin α6β4 are the main components [12], we found that the most affected gene associated with the extracellular matrix and doi:10.1371/journal.pone.0140942.g008

Summary

Introduction

Interleukin (IL)-1 is closely associated with inflammatory tissue destruction in rheumatoid arthritis and periodontitis [1, 2]. Clinical studies indicate elevation of IL-1β and IL-1α levels in gingival tissue and gingival crevicular fluid (GCF) from periodontitis patients compared with healthy subjects [3, 4]. IL-1Ra levels in GCF are negatively correlated with the disease severity of chronic periodontitis patients [3]. IL-1Ra knockout (KO) mice with a BALB/ca background spontaneously develop chronic inflammatory polyarthropathy that closely resembles arthritis in humans [8]. Because infection with Aggregatibacter actinomycetemcomitans establishes an experimental periodontitis model, A. actinomycetemcomitans lipopolysaccharide (LPS)-stimulated culture supernatants from IL-1Ra KO mouse peritoneal macrophages induce severe calvarial bone resorption compared with those from wild-type (WT) mice [10]. Live A. actinomycetemcomitansinfected IL-1Ra KO mice as an experimental periodontitis model show histological apical migration of the junctional epithelium as well as epithelial attachment loss in periodontal tissue [11]

Methods

Results

Conclusion