Convergent Research Consortium in Immunologic Disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Department of Rheumatology, Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, Korea.
Sci Rep. 2017 Apr 26;7(1):1197. doi: 10.1038/s41598-017-01101-y.
Histamine H4 receptor (H4R) has immune-modulatory and chemotaxic effects in various immune cells. This study aimed to determine the osteoclastogenic role of H4R in rheumatoid arthritis (RA). The concentration of histamine in synovial fluid (SF) and sera in patients with RA was measured using ELISA. After RA SF and peripheral blood (PB) CD14+ monocytes were treated with histamine, IL-17, IL-21 and IL-22, and a H4R antagonist (JNJ7777120), the gene expression H4R and RANKL was determined by real-time PCR. Osteoclastogenesis was assessed by counting TRAP-positive multinucleated cells in PB CD14+ monocytes cultured with histamine, Th17 cytokines and JNJ7777120. SF and serum concentration of histamine was higher in RA, compared with osteoarthritis and healthy controls. The expression of H4R was increased in PB monocytes in RA patients. Histamine, IL-6, IL-17, IL-21 and IL-22 induced the expression of H4R in monocytes. Histamine, IL-17, and IL-22 stimulated RANKL expression in RA monocytes and JNJ7777120 reduced the RANKL expression. Histamine and Th17 cytokines induced the osteoclast differentiation from monocytes and JNJ7777120 decreased the osteoclastogenesis. H4R mediates RANKL expression and osteoclast differentiation induced by histamine and Th17 cytokines. The blockage of H4R could be a new therapeutic modality for prevention of bone destruction in RA.
组胺 H4 受体（H4R）在各种免疫细胞中具有免疫调节和趋化作用。本研究旨在确定 H4R 在类风湿关节炎（RA）中的破骨细胞生成作用。采用 ELISA 法检测 RA 患者滑膜液（SF）和血清中组胺的浓度。用组胺、IL-17、IL-21 和 IL-22 处理 RA SF 和外周血（PB）CD14+单核细胞后，用实时 PCR 测定 H4R 和 RANKL 的基因表达。通过计数 PB CD14+单核细胞在组胺、Th17 细胞因子和 JNJ7777120 培养物中形成的 TRAP 阳性多核细胞来评估破骨细胞生成。与骨关节炎和健康对照组相比，RA 患者 SF 和血清中组胺浓度升高。RA 患者 PB 单核细胞中 H4R 的表达增加。组胺、IL-6、IL-17、IL-21 和 IL-22 诱导单核细胞中 H4R 的表达。组胺、IL-17 和 IL-22 刺激 RA 单核细胞中 RANKL 的表达，而 JNJ7777120 降低 RANKL 的表达。组胺和 Th17 细胞因子诱导单核细胞向破骨细胞分化，而 JNJ7777120 则减少破骨细胞生成。H4R 介导组胺和 Th17 细胞因子诱导的 RANKL 表达和破骨细胞分化。阻断 H4R 可能成为预防 RA 骨破坏的新治疗方法。
