Tada Hiroyuki, Shimizu Takamitsu, Matsushita Kenji, Takada Haruhiko
Division of Oral Microbiology, Tohoku University Graduate School of Dentistry.
Department of Oral Disease Research, National Center for Geriatrics and Gerontology.
Biomed Res. 2017;38(3):167-173. doi: 10.2220/biomedres.38.167.
hCAP-18/LL-37 is an antimicrobial peptide that is mainly expressed in epithelial cells. Gingival epithelial cells play pivotal roles in antimicrobial defense by expressing hCAP-18/LL-37. Porphyromonas gingivalis is a primary pathogen for chronic periodontitis and produces cysteine proteinase gingipains, which induce proinflammatory cytokines production, leading to enhance inflammatory responses. In contrast, gingipains attenuate immune responses, leading to induce anti-inflammatory responses. In this study, we investigated the ability of gingipains to attenuate P. gingivalis-induced hCAP-18/LL-37 production by human gingival epithelial Ca9-22 cells. The expression of LL-37 mRNA was increased by the infection of Ca9-22 cells with a P. gingivalis gingipains-null mutant KDP136 compared with P. gingivalis wild-type strain ATCC 33277. Interleukin (IL)-33 is involved in the development of chronic inflammatory diseases, and P. gingivalis infection increases IL-33 production by human gingival epithelial cells. P. gingivalis-induced LL-37 mRNA expression was augmented in IL-33 small interfering RNA-transfected Ca9-22 cells. Maxacalcitol (22-oxacalcitriol: OCT) is a biologically active metabolite of vitamin D analog, and OCT increases hCAP-18/LL-37 production by human gingival epithelial cells. The increasing expression of LL-37 mRNA by OCT was down-regulated by infection of the cells with P. gingivalis ATCC 33277 in Ca9-22 cells. Furthermore, P. gingivalis infection induced IL-33 mRNA expression in Ca9-22 cells; therefore, P. gingivalis-induced endogenous IL-33 down-regulated hCAP-18/LL-37 production by the bacterium. These findings suggested that endogenous IL-33 down-regulates the induction of hCAP-18/LL-37 production in human gingival epithelial cells.
人阳离子抗菌蛋白18/LL-37是一种主要在上皮细胞中表达的抗菌肽。牙龈上皮细胞通过表达人阳离子抗菌蛋白18/LL-37在抗菌防御中发挥关键作用。牙龈卟啉单胞菌是慢性牙周炎的主要病原体，可产生半胱氨酸蛋白酶牙龈蛋白酶，其可诱导促炎细胞因子的产生，从而增强炎症反应。相反，牙龈蛋白酶可减弱免疫反应，进而诱导抗炎反应。在本研究中，我们调查了牙龈蛋白酶减弱牙龈卟啉单胞菌诱导人牙龈上皮Ca9-22细胞产生人阳离子抗菌蛋白18/LL-37的能力。与牙龈卟啉单胞菌野生型菌株ATCC 33277相比，用牙龈卟啉单胞菌牙龈蛋白酶缺失突变体KDP136感染Ca9-22细胞可增加LL-37 mRNA的表达。白细胞介素（IL）-33参与慢性炎症性疾病的发展，牙龈卟啉单胞菌感染可增加人牙龈上皮细胞中IL-33的产生。在IL-33小干扰RNA转染的Ca9-22细胞中，牙龈卟啉单胞菌诱导的LL-37 mRNA表达增加。马沙骨化醇（22-氧代骨化三醇：OCT）是维生素D类似物的一种生物活性代谢产物，OCT可增加人牙龈上皮细胞中人阳离子抗菌蛋白/LL-37的产生。在Ca9-22细胞中，用牙龈卟啉单胞菌ATCC 33277感染细胞可下调OCT诱导LL-37 mRNA表达的增加。此外，牙龈卟啉单胞菌感染可诱导Ca9-22细胞中IL-33 mRNA的表达；因此，牙龈卟啉单胞菌诱导的内源性IL-33可下调该细菌诱导的人阳离子抗菌蛋白18/LL-37的产生。这些发现表明内源性IL-33可下调人牙龈上皮细胞中人阳离子抗菌蛋白18/LL-37产生的诱导。
