Porphyromonas gingivalis Gingipain-Dependently Enhances IL-33 Production in Human Gingival Epithelial Cells

Hiroyuki Tada; Takashi Matsuyama; Takashi Nishioka; Makoto Hagiwara; Yusuke Kiyoura; Hidetoshi Shimauchi; Kenji Matsushita

doi:10.1371/journal.pone.0152794

Porphyromonas gingivalis Gingipain-Dependently Enhances IL-33 Production in Human Gingival Epithelial Cells

PLoS One. 2016 Apr 8;11(4):e0152794. doi: 10.1371/journal.pone.0152794. eCollection 2016.

Authors

Hiroyuki Tada^{1

2}, Takashi Matsuyama³, Takashi Nishioka⁴, Makoto Hagiwara¹, Yusuke Kiyoura⁵, Hidetoshi Shimauchi⁶, Kenji Matsushita¹

Affiliations

¹ Department of Oral Disease Research, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan.
² Division of Oral Microbiology, Tohoku University Graduate School of Dentistry, Sendai, Miyagi, Japan.
³ Department of Periodontology, Kagoshima University Graduate School of Medical and Dental Sciences, Sakuragaoka, Kagoshima, Japan.
⁴ Division of Oral Diagnosis, Tohoku University Graduate School of Dentistry, Sendai, Miyagi, Japan.
⁵ Department of Oral Medical Science, Ohu University School of Dentistry, Koriyama, Fukushima, Japan.
⁶ Division of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry, Sendai, Miyagi, Japan.

Abstract

The cytokine IL-33 is constitutively expressed in epithelial cells and it augments Th2 cytokine-mediated inflammatory responses by regulating innate immune cells. We aimed to determine the role of the periodontal pathogen, Porphyromonas gingivalis, in the enhanced expression of IL-33 in human gingival epithelial cells. We detected IL-33 in inflamed gingival epithelium from patients with chronic periodontitis, and found that P. gingivalis increased IL-33 expression in the cytoplasm of human gingival epithelial cells in vitro. In contrast, lipopolysaccharide, lipopeptide, and fimbriae derived from P. gingivalis did not increase IL-33 expression. Specific inhibitors of P. gingivalis proteases (gingipains) suppressed IL-33 mRNA induction by P. gingivalis and the P. gingivalis gingipain-null mutant KDP136 did not induce IL-33 expression. A small interfering RNA for protease-activated receptor-2 (PAR-2) as well as inhibitors of phospholipase C, p38 and NF-κB inhibited the expression of IL-33 induced by P. gingivalis. These results indicate that the PAR-2/IL-33 axis is promoted by P. gingivalis infection in human gingival epithelial cells through a gingipain-dependent mechanism.

Publication types

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

MeSH terms

Adhesins, Bacterial / pharmacology*
Blotting, Western
Carcinoma, Squamous Cell / drug therapy
Carcinoma, Squamous Cell / metabolism*
Carcinoma, Squamous Cell / pathology
Case-Control Studies
Cells, Cultured
Cysteine Endopeptidases / pharmacology*
Cytokines / genetics
Cytokines / metabolism
Epithelial Cells / cytology
Epithelial Cells / drug effects
Epithelial Cells / metabolism*
Fluorescent Antibody Technique
Gingipain Cysteine Endopeptidases
Gingiva / cytology
Gingiva / drug effects
Gingiva / metabolism*
Humans
Immunoenzyme Techniques
Interleukin-33 / genetics
Interleukin-33 / metabolism*
Periodontitis / drug therapy
Periodontitis / metabolism*
Periodontitis / pathology
Porphyromonas gingivalis / physiology*
RNA, Messenger / genetics
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction

Substances

Adhesins, Bacterial
Cytokines
Gingipain Cysteine Endopeptidases
Interleukin-33
RNA, Messenger
Cysteine Endopeptidases

Grants and funding

This work was supported by Grand-in-Aids for Scientific Research (25463225 to HT, 22390354 to KM) from the Japan Society for the Promotion of Science; and the Takeda Science Foundation (HT). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.