PER2 is downregulated by the LPS-induced inflammatory response in synoviocytes in rheumatoid arthritis and is implicated in disease susceptibility

Lee, Hwa Young; Nah, Seong‐Su; Chang, Sung Hae; Kim, Hyung‐Ki; Kwon, Jun-Tack; Lee, Sang‐Hyun; Cho, Ik‐Hyun; Lee, Sang Won; Kim, Young Ock; Hong, Seung‐Jae; Kim, Hak-Jae

doi:10.3892/mmr.2017.6578

Cited by 16 publications

(15 citation statements)

References 43 publications

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“…Previous research has demonstrated that Per2 expression was reduced in non-tumourigenic breast epithelial cells stimulated by IL-6 [33]. Further, immunoblotting analysis showed the Per2 protein expression was inhibited in LPS-treated rheumatoid arthritis synovial cells [34]. In the present study, Per2 mRNA expression was markedly lower in NHAC-kn cells treated by LPS than normal NHAC-kn cells.…”

Section: Discussionsupporting

confidence: 55%

Per2 attenuates LPS-induced chondrocyte injury through the PTEN/PI3K/Akt signalling pathway

Zhao¹,

Ma²,

Dong³

et al. 2020

Bioscience Reports

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This research aimed to explore the role of period circadian clock 2 (Per2) in the evolution of osteoarthritis (OA) and the relevant mechanisms. Per2 messenger RNA (mRNA) and protein levels were markedly reduced in NHAC-kn cells treated with 5 µg/ml lipopolysaccharide (LPS) for 12 h. Then, pcDNA3.1-Per2 and si-Per2 were recruited to boost and reduce the expression of Per2, respectively. MTT assay, apoptosis analysis and enzyme-linked immunosorbent assay (ELISA) results showed that Per2 increased cell proliferation, while inhibited apoptosis and inflammation. Furthermore, the PTEN/PI3K/Akt signalling pathway was activated by Per2 overexpression; the CO-IP data confirmed that Per2 specifically bound to PTEN. Through employing IGF-1, a PI3K activator, we determined that Per2-mediated inflammation response in LPS-stimulated NHAC-kn cells through the PTEN/PI3K/Akt signalling pathway. In summary, the present study indicates that Per2 may serve as a novel therapeutic target through activating the PTEN/PI3K/Akt signalling pathway.

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Section: Discussionsupporting

confidence: 55%

Per2 attenuates LPS-induced chondrocyte injury through the PTEN/PI3K/Akt signalling pathway

Zhao¹,

Ma²,

Dong³

et al. 2020

Bioscience Reports

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“…LPS is a potent endotoxin involved in the progression of RA diseases (36). LPS treatment (100 ng/ml) for 12 h markedly increased the mRNA and protein expression levels of TNF-α, IL-1β, IL-6 and IL-8 in the PBMCs of patients with RA by between 3- and 10-fold (Fig.…”

Section: Resultsmentioning

confidence: 99%

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

Zhou

Luo

et al. 2019

Mol Med Report

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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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“…This causes tissue destruction via MAC (Cao et al, 2017 ) and exacerbating effector cell inflammation (Perez-Aso et al, 2013 ; Sadik et al, 2018 ). Although anti-inflammatory components, such as HO-1 are also induced in the synovial joints, the levels of HO-1 are shown to decline with the advanced immunopathogenesis of RA (Kitamura et al, 2011 ; May et al, 2018 ), which is presumably moderated by the RA-driven proinflammatory circadian responses (Lee et al, 2017 ). Thus, the second regulatory loop of the core transcriptional circadian clock proteins also plays an important role in immune response and complement signaling ( Figure 2 -top blue panel 2; bottom orange panel).…”

Section: Complement and Circadian Signalingmentioning

confidence: 99%

Circadian Clock and Complement Immune System—Complementary Control of Physiology and Pathology?

Shivshankar

Fekry

Eckel‐Mahan

et al. 2020

Front. Cell. Infect. Microbiol.

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Mammalian species contain an internal circadian (i.e., 24-h) clock that is synchronized to the day and night cycles. Large epidemiological studies, which are supported by carefully controlled studies in numerous species, support the idea that chronic disruption of our circadian cycles results in a number of health issues, including obesity and diabetes, defective immune response, and cancer. Here we focus specifically on the role of the complement immune system and its relationship to the internal circadian clock system. While still an incompletely understood area, there is evidence that dysregulated proinflammatory cytokines, complement factors, and oxidative stress can be induced by circadian disruption and that these may feed back into the oscillator at the level of circadian gene regulation. Such a feedback cycle may contribute to impaired host immune response against pathogenic insults. The complement immune system including its activated anaphylatoxins, C3a and C5a, not only facilitate innate and adaptive immune response in chemotaxis and phagocytosis, but they can also amplify chronic inflammation in the host organism. Consequent development of autoimmune disorders, and metabolic diseases associated with additional environmental insults that activate complement can in severe cases, lead to accelerated tissue dysfunction, fibrosis, and ultimately organ failure. Because several promising complement-targeted therapeutics to block uncontrolled complement activation and treat autoimmune diseases are in various phases of clinical trials, understanding fully the circadian properties of the complement system, and the reciprocal regulation by these two systems could greatly improve patient treatment in the long term.

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PER2 is downregulated by the LPS-induced inflammatory response in synoviocytes in rheumatoid arthritis and is implicated in disease susceptibility

Cited by 16 publications

References 43 publications

Per2 attenuates LPS-induced chondrocyte injury through the PTEN/PI3K/Akt signalling pathway

Per2 attenuates LPS-induced chondrocyte injury through the PTEN/PI3K/Akt signalling pathway

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

Circadian Clock and Complement Immune System—Complementary Control of Physiology and Pathology?

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