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

Goto H, Ishihara Y, Kikuchi T, Izawa A, Ozeki N, Okabe E, Kamiya Y, Ozawa Y, Mizutani H, Yamamoto G, Mogi M, Nakata K, Maeda H, Noguchi T, Mitani A - PLoS ONE (2015)

Bottom Line: These results suggested that continuous supply of IL-1 had no effect on the induction of MMP-13 by IL-1Ra siRNA.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 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Periodontology, School of Dentistry, Aichi Gakuin University, Chikusa-ku, Nagoya, Aichi, 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.

No MeSH data available.


Related in: MedlinePlus

Investigation of the expression of genes involved in cell–cell and cell–matrix interactions using a PCR array.The graph shows the fold changes of gene expression in IL-1Ra and control siRNA-transfected Ca9-22 cells. MMP-13 was up-regulated in IL-1Ra siRNA-transfected cells by 4.8-fold (n = 6). The red circle (most up-regulated gene) indicates MMP-13 expression in the graph. TIMP-1 and TIMP-2 expression levels are indicated by arrows.
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pone.0140942.g001: Investigation of the expression of genes involved in cell–cell and cell–matrix interactions using a PCR array.The graph shows the fold changes of gene expression in IL-1Ra and control siRNA-transfected Ca9-22 cells. MMP-13 was up-regulated in IL-1Ra siRNA-transfected cells by 4.8-fold (n = 6). The red circle (most up-regulated gene) indicates MMP-13 expression in the graph. TIMP-1 and TIMP-2 expression levels are indicated by arrows.

Mentions: A human extracellular matrix and adhesion molecules PCR array was used to investigate differences in the expression of 84 genes involved in cell–cell and cell–matrix interactions. Fig 1 shows the fold changes in expression between control and IL-1Ra siRNA-transfected cells after incubation for 6 hours. Among the 84 genes, MMP-13 mRNA expression (indicated by the red circle) was up-regulated by 4.8-fold in IL-1Ra siRNA-transfected cells compared with control siRNA-transfected cells. MMP-13 activity is precisely regulated after its secretion at the post-translational level as a precursor zymogen before activation and endogenous tissue inhibitors of metalloproteinases referred to as TIMPs. Although studies have already shown that TIMP-2 is induced by cytokines, TIMP-1 and TIMP-2 expression levels (indicated by arrows) were unchanged in IL-1Ra siRNA-transfected cells compared with the control.


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

Goto H, Ishihara Y, Kikuchi T, Izawa A, Ozeki N, Okabe E, Kamiya Y, Ozawa Y, Mizutani H, Yamamoto G, Mogi M, Nakata K, Maeda H, Noguchi T, Mitani A - PLoS ONE (2015)

Investigation of the expression of genes involved in cell–cell and cell–matrix interactions using a PCR array.The graph shows the fold changes of gene expression in IL-1Ra and control siRNA-transfected Ca9-22 cells. MMP-13 was up-regulated in IL-1Ra siRNA-transfected cells by 4.8-fold (n = 6). The red circle (most up-regulated gene) indicates MMP-13 expression in the graph. TIMP-1 and TIMP-2 expression levels are indicated by arrows.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4608771&req=5

pone.0140942.g001: Investigation of the expression of genes involved in cell–cell and cell–matrix interactions using a PCR array.The graph shows the fold changes of gene expression in IL-1Ra and control siRNA-transfected Ca9-22 cells. MMP-13 was up-regulated in IL-1Ra siRNA-transfected cells by 4.8-fold (n = 6). The red circle (most up-regulated gene) indicates MMP-13 expression in the graph. TIMP-1 and TIMP-2 expression levels are indicated by arrows.
Mentions: A human extracellular matrix and adhesion molecules PCR array was used to investigate differences in the expression of 84 genes involved in cell–cell and cell–matrix interactions. Fig 1 shows the fold changes in expression between control and IL-1Ra siRNA-transfected cells after incubation for 6 hours. Among the 84 genes, MMP-13 mRNA expression (indicated by the red circle) was up-regulated by 4.8-fold in IL-1Ra siRNA-transfected cells compared with control siRNA-transfected cells. MMP-13 activity is precisely regulated after its secretion at the post-translational level as a precursor zymogen before activation and endogenous tissue inhibitors of metalloproteinases referred to as TIMPs. Although studies have already shown that TIMP-2 is induced by cytokines, TIMP-1 and TIMP-2 expression levels (indicated by arrows) were unchanged in IL-1Ra siRNA-transfected cells compared with the control.

Bottom Line: These results suggested that continuous supply of IL-1 had no effect on the induction of MMP-13 by IL-1Ra siRNA.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 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Periodontology, School of Dentistry, Aichi Gakuin University, Chikusa-ku, Nagoya, Aichi, 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.

No MeSH data available.


Related in: MedlinePlus