Activation of TGR5 alleviates inflammation in rheumatoid arthritis peripheral blood mononuclear cells and in mice with collagen II‑induced arthritis

Li,Zhe‑Yong; Zhou,Jing‑Jing; Luo,Chun‑Lei; Zhang,Le‑Meng

doi:10.3892/mmr.2019.10711

Activation of TGR5 alleviates inflammation in rheumatoid arthritis peripheral blood mononuclear cells and in mice with collagen II‑induced arthritis

Authors:
- Zhe‑Yong Li
- Jing‑Jing Zhou
- Chun‑Lei Luo
- Le‑Meng Zhang
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Affiliations: Department of General Surgery, Sir Run Run Shaw Hospital, Hangzhou, Zhejiang 310017, P.R. China, Department of Rheumatology, Navy General Hospital, Beijing 100048, P.R. China, Department of Nephrology, Ningbo First Hospital, Ningbo, Zhejiang 3150102, P.R. China, Thoracic Medicine Department 1, Hunan Cancer Hospital, Changsha, Hunan 410013, P.R. China
Published online on: September 26, 2019 https://doi.org/10.3892/mmr.2019.10711
Pages: 4540-4550
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Rheumatoid arthritis (RA) is characterized by chronic inﬂammatory synovitis resulting in progressive joint destruction. Persistent synovial inflammation is induced by activation of various inﬂammatory cells. G‑protein‑coupled bile acid receptor 1 (TGR5) is a G‑protein‑coupled receptor activated by various bile acids, which has been reported to act as a key adaptor in regulating various signaling pathways involved in inflammatory responses and a diverse array of physiological processes, including bile acid synthesis, lipid and carbohydrate metabolism, carcinogenesis, immunity and inflammation. In the present study, TGR5 expression was detected in RA peripheral blood mononuclear cells (PBMCs), and its association with clinical disease activity, histological synovitis severity and radiological joint destruction was analyzed. Subsequently, the role and potential underlying mechanisms of TGR5 in the PBMCs of patients with RA and mice with collagen II‑induced arthritis (CIA) were investigated. PBMCs were obtained from 50 patients with RA and 40 healthy controls (HCs). The mRNA and protein expression levels of TGR5 were detected in PBMCs via reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and immunofluorescence staining, respectively. Additionally, the levels of proinflammatory cytokines were analyzed by RT‑qPCR and enzyme‑linked immunosorbent assay (ELISA). The activation of nuclear factor‑κB (NF‑κB) and IκB kinase a was determined via western blot analysis. The anti‑arthritic and anti‑inflammatory effects of LCA on mice with CIA were then investigated. The arthritis score was assessed, and the protein levels of proinflammatory cytokines in the plasma of mice were detected via ELISA. TGR5 mRNA expression was significantly downregulated in the PBMCs of patients with RA compared with in those of the HCs (0.53±0.58 for patients vs. 1.49±0.83 for HCs; P<0.001); similar findings were observed at the protein level. The mRNA expression levels of TGR5 in the PBMCs of patients with RA with a high 28‑Joint Disease Activity Score (DAS28) were significantly decreased compared with in patients with a low DAS28 (0.81±0.65 for low score vs. 0.35±0.46 for high score; P=0.002). Furthermore, TGR5 expression was significantly correlated with the levels of C‑reactive protein (r=‑0.429; P=0.002) and the DAS28 (r=‑0.383; P=0.006). RT‑qPCR and ELISA analyses indicated that lithocholic acid (LCA, 10 mg/kg/day) attenuated lipopolysaccharide‑induced proinflammatory cytokine production via inhibition of NF‑κB activity in the PBMCs of patients with RA. In addition, the arthritis score was significantly decreased in LCA‑treated CIA mice compared with in non‑treated CIA mice. The increased production of tumor necrosis factor‑α, interleukin (IL)‑1β, IL‑6 and IL‑8 was significantly reduced in the plasma of LCA‑treated CIA mice compared with the control. In conclusion, TGR5 may contribute to the inflammation of PBMCs in patients with RA and mice with CIA.

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