Cathepsin S Is Involved in Th17 Differentiation Through the Upregulation of IL-6 by Activating PAR-2 after Systemic Exposure to Lipopolysaccharide from Porphyromonas gingivalis

Masato Dekita, Zhou Wu, Junjun Ni, Xinwen Zhang, Yicong Liu, Xu Yan, Hiroshi Nakanishi, Ichiro Takahashi

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Positive links have been found between periodontitis and numerous diseases in humans via persistent inflammation throughout the body. However, the main factors responsible for maintaining this pro-inflammatory condition are poorly understood. The spleen, the largest secondary immune organ, is a central hub regulating the immune response/inflammation due to the dendritic cell (DC) response to CD4(+) T cell subtype differentiation, and lysosomal proteinase cathepsin S (CatS) is known to be involved in DC functions. In the present study, we found that CatS-induced IL-6 production by splenic DCs subsequently promotes Th17 differentiation, in response to systemic exposure to lipopolysaccharide derived from Porphyromonas gingivalis (PgLPS). The population of CD11c(+) DCs was significantly increased in the splenic marginal zone (MZ) locally of wild-type (DBA/2) mice with splenomegaly but not in that of CatS deficient (CatS(-/-) ) mice after systemic exposure to PgLPS for 7 consecutive days (5 mg/kg/day, intraperitoneal). Similarly, the population of Th17(+)CD4(+) T cells was also significantly increased in the splenic MZ of wild-type mice but not in that of CatS(-/-) mice after PgLPS exposure. Furthermore, the increase in the Th17(+) CD4(+) T cell population paralleled increases in the levels of CatS and IL-6 in CD11c(+) cells in the splenic MZ. In isolated primary splenic CD11c(+) cells, the mRNA expression and the production of IL-6 was dramatically increased in wild-type mice but not in CatS(-)(/-) mice after direct stimulation with PgLPS (1 μg/ml), and this PgLPS-induced increase in the IL-6 expression was completely abolished by pre-treatment with Z-Phe-Leu-COCHO (Z-FL), the specific inhibitor of CatS. The PgLPS activated protease-activated receptor (PAR) 2 in the isolated splenic CD11c(+) cells was also significantly inhibited by CatS deficiently. In addition, the PgLPS-induced increase in the IL-6 production by splenic CD11c(+) cells was completely abolished by pre-treatment with FSLLRY-NH2, a PAR2 antagonist, as well as Akti, a specific inhibitor of Akt. These findings indicate that CatS plays a critical role in driving splenic DC-dependent Th17 differentiation through the upregulation of IL-6 by activating PAR2 after exposure to components of periodontal bacteria. Therefore, CatS-specific inhibitors may be effective in alleviating periodontitis-related immune/inflammation.

Original languageEnglish
Pages (from-to)470
JournalFrontiers in Pharmacology
Volume8
DOIs
Publication statusPublished - 2017

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cathepsin S
PAR-2 Receptor
Porphyromonas gingivalis
Lipopolysaccharides
Interleukin-6
Cats
Up-Regulation
Dendritic Cells
Periodontitis
Inflammation
T-Lymphocytes
Population
Inbred DBA Mouse

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Cathepsin S Is Involved in Th17 Differentiation Through the Upregulation of IL-6 by Activating PAR-2 after Systemic Exposure to Lipopolysaccharide from Porphyromonas gingivalis. / Dekita, Masato; Wu, Zhou; Ni, Junjun; Zhang, Xinwen; Liu, Yicong; Yan, Xu; Nakanishi, Hiroshi; Takahashi, Ichiro.

In: Frontiers in Pharmacology, Vol. 8, 2017, p. 470.

Research output: Contribution to journalArticle

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title = "Cathepsin S Is Involved in Th17 Differentiation Through the Upregulation of IL-6 by Activating PAR-2 after Systemic Exposure to Lipopolysaccharide from Porphyromonas gingivalis",
abstract = "Positive links have been found between periodontitis and numerous diseases in humans via persistent inflammation throughout the body. However, the main factors responsible for maintaining this pro-inflammatory condition are poorly understood. The spleen, the largest secondary immune organ, is a central hub regulating the immune response/inflammation due to the dendritic cell (DC) response to CD4(+) T cell subtype differentiation, and lysosomal proteinase cathepsin S (CatS) is known to be involved in DC functions. In the present study, we found that CatS-induced IL-6 production by splenic DCs subsequently promotes Th17 differentiation, in response to systemic exposure to lipopolysaccharide derived from Porphyromonas gingivalis (PgLPS). The population of CD11c(+) DCs was significantly increased in the splenic marginal zone (MZ) locally of wild-type (DBA/2) mice with splenomegaly but not in that of CatS deficient (CatS(-/-) ) mice after systemic exposure to PgLPS for 7 consecutive days (5 mg/kg/day, intraperitoneal). Similarly, the population of Th17(+)CD4(+) T cells was also significantly increased in the splenic MZ of wild-type mice but not in that of CatS(-/-) mice after PgLPS exposure. Furthermore, the increase in the Th17(+) CD4(+) T cell population paralleled increases in the levels of CatS and IL-6 in CD11c(+) cells in the splenic MZ. In isolated primary splenic CD11c(+) cells, the mRNA expression and the production of IL-6 was dramatically increased in wild-type mice but not in CatS(-)(/-) mice after direct stimulation with PgLPS (1 μg/ml), and this PgLPS-induced increase in the IL-6 expression was completely abolished by pre-treatment with Z-Phe-Leu-COCHO (Z-FL), the specific inhibitor of CatS. The PgLPS activated protease-activated receptor (PAR) 2 in the isolated splenic CD11c(+) cells was also significantly inhibited by CatS deficiently. In addition, the PgLPS-induced increase in the IL-6 production by splenic CD11c(+) cells was completely abolished by pre-treatment with FSLLRY-NH2, a PAR2 antagonist, as well as Akti, a specific inhibitor of Akt. These findings indicate that CatS plays a critical role in driving splenic DC-dependent Th17 differentiation through the upregulation of IL-6 by activating PAR2 after exposure to components of periodontal bacteria. Therefore, CatS-specific inhibitors may be effective in alleviating periodontitis-related immune/inflammation.",
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AU - Dekita, Masato

AU - Wu, Zhou

AU - Ni, Junjun

AU - Zhang, Xinwen

AU - Liu, Yicong

AU - Yan, Xu

AU - Nakanishi, Hiroshi

AU - Takahashi, Ichiro

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AB - Positive links have been found between periodontitis and numerous diseases in humans via persistent inflammation throughout the body. However, the main factors responsible for maintaining this pro-inflammatory condition are poorly understood. The spleen, the largest secondary immune organ, is a central hub regulating the immune response/inflammation due to the dendritic cell (DC) response to CD4(+) T cell subtype differentiation, and lysosomal proteinase cathepsin S (CatS) is known to be involved in DC functions. In the present study, we found that CatS-induced IL-6 production by splenic DCs subsequently promotes Th17 differentiation, in response to systemic exposure to lipopolysaccharide derived from Porphyromonas gingivalis (PgLPS). The population of CD11c(+) DCs was significantly increased in the splenic marginal zone (MZ) locally of wild-type (DBA/2) mice with splenomegaly but not in that of CatS deficient (CatS(-/-) ) mice after systemic exposure to PgLPS for 7 consecutive days (5 mg/kg/day, intraperitoneal). Similarly, the population of Th17(+)CD4(+) T cells was also significantly increased in the splenic MZ of wild-type mice but not in that of CatS(-/-) mice after PgLPS exposure. Furthermore, the increase in the Th17(+) CD4(+) T cell population paralleled increases in the levels of CatS and IL-6 in CD11c(+) cells in the splenic MZ. In isolated primary splenic CD11c(+) cells, the mRNA expression and the production of IL-6 was dramatically increased in wild-type mice but not in CatS(-)(/-) mice after direct stimulation with PgLPS (1 μg/ml), and this PgLPS-induced increase in the IL-6 expression was completely abolished by pre-treatment with Z-Phe-Leu-COCHO (Z-FL), the specific inhibitor of CatS. The PgLPS activated protease-activated receptor (PAR) 2 in the isolated splenic CD11c(+) cells was also significantly inhibited by CatS deficiently. In addition, the PgLPS-induced increase in the IL-6 production by splenic CD11c(+) cells was completely abolished by pre-treatment with FSLLRY-NH2, a PAR2 antagonist, as well as Akti, a specific inhibitor of Akt. These findings indicate that CatS plays a critical role in driving splenic DC-dependent Th17 differentiation through the upregulation of IL-6 by activating PAR2 after exposure to components of periodontal bacteria. Therefore, CatS-specific inhibitors may be effective in alleviating periodontitis-related immune/inflammation.

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