Kurarinone Attenuates Collagen-Induced Arthritis in Mice by Inhibiting Th1/Th17 Cell Responses and Oxidative Stress.

Kuo-Tung Tang,Shih-Chao Lin,Chi-Chien Lin,Jou-Hsuan Wang,Sen-Wei Tsai

doi:10.3390/ijms22084002

Abstract

Kurarinone is a flavanone, extracted from Sophora flavescens Aiton, with multiple biological effects. Here, we determine the therapeutic potential of kurarinone and elucidate the interplay between kurarinone and the autoimmune disease rheumatoid arthritis (RA). Arthritis was recapitulated by induction of bovine collagen II (CII) in DBA/1 mice as a collagen-induced arthritis (CIA) model. After the establishment of the CIA, kurarinone was given orally from day 21 to 42 (100 mg/kg/day) followed by determination of the severity based on a symptom scoring scale and with histopathology. Levels of cytokines, anti-CII antibodies, and the proliferation and lineages of T cells from the draining lymph nodes were measured using ELISA and flow cytometry, respectively. The expressional changes, including STAT1, STAT3, Nrf2, KEAP-1, and heme oxygenase-1 (HO-1) changes in the paw tissues, were evaluated by Western blot assay. Oxidative stress featured with malondiadehyde (MDA) and hydrogen peroxide (H2O2) activities in paw tissues were also evaluated. Results showed that kurarinone treatment reduced arthritis severity of CIA mice, as well as their levels of proinflammatory cytokines, TNF-α, IL-6, IFN-γ, and IL-17A, in the serum and paw tissues. T cell proliferation was also reduced by kurarinone even under the stimulation of CII and anti-CD3 antibody. In addition, kurarinone reduced STAT1 and STAT3 phosphorylation and the proportions of Th1 and Th17 cells in lymph nodes. Moreover, kurarinone suppressed the production of MDA and H2O2. All while promoting enzymatic activities of key antioxidant enzymes, SOD and GSH-Px. In the paw tissues, upregulation of Nrf-2 and HO-1, and downregulation of KEAP-1 were observed. Overall, kurarinone showed an anti-inflammatory effect by inhibiting Th1 and Th17 cell differentiation and an antioxidant effect exerted in part through activating the Nrf-2/KEAP-1 pathway. These beneficial effects in CIA mice contributed to the amelioration of their arthritis, indicating that kurarinone might be an adjunct treatment option for rheumatoid arthritis.

Highlights

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation, cartilage damage, and joint destruction [1], that leads to negative impacts on the physical movement and life quality of patients
Kurarinone showed an anti-inflammatory effect by inhibiting Th1 and Th17 cell differentiation and an antioxidant effect exerted in part through activating the Nrf-2/KEAP-1 pathway
Experiments utilizing the collagen-induced arthritis (CIA) animal model have indicated the involvement of activated pro-inflammatory Th1 and Th17 cells and suppressed Treg cells could be involved in the RA pathogenesis [7]

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation, cartilage damage, and joint destruction [1], that leads to negative impacts on the physical movement and life quality of patients. The systemic inflammatory response targets the synovial membrane, leading to joint destruction through cartilage degradation and osteoclast activation [5,6]. Experiments utilizing the collagen-induced arthritis (CIA) animal model have indicated the involvement of activated pro-inflammatory Th1 and Th17 cells and suppressed Treg cells could be involved in the RA pathogenesis [7]. A result of accumulated reactive oxygen species (ROS), contributes to the synovitis development in RA. ROS can degrade proteoglycans and hypochlorous acid (HOCl) in the cartilage, leading to collagen fragmentations and proteoglycan synthesis suppression [8,9]. Increased oxidative stress has been reported in RA patients [10]

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Results

Conclusion