AB0127 Anti-inflammatory and pro-apoptosis effects of 18beta-glycyrrhetinic acid in in vivo and in vitro models of rheumatoid arthritis
Authors: M. Wang, R. Huang
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Rheumatoid arthritis (RA) is one of the most common autoimmune diseases and it affects 0.5%–2.0% of the human population worldwide.<sup>1</sup>Though disease modifying anti-rheumatic drugs (DMARDs) can improve the clinical condition of patients with RA, toxicities of these drugs will be accumulated with long-term use and the unwanted side effects still cannot be avoided. 18β-glycyrrhetinic acid (18β-GA), an active component of licorice, exhibits potential anti-cancer, anti-inflammatory, anti-allergic, and anti-microbial activities.<sup>2</sup> Moreover, 18β-GA has been elucidated to attenuate hepatotoxicity or nephrotoxicity caused by chemical drugs, included methotrexate(MTX)[.<sup>2</sup> These evidences suggested 18 β-GA may become a candidate for low toxicity RA therapy as the mechanism was revealed. <h3>Objectives</h3> The aim of this study is to investigate the underline mechanism of 18β-GA on anti-inflammation and anti-proliferation in <i>in vivo</i> and <i>in vitro</i> models of RA. <h3>Methods</h3> CIA rats were treated with 18β-GA, methotrexate, celecoxib and three combination therapies for 30 days. Paw swelling volume, thromboxane synthase (TxAS), proliferating cell nuclear antigenprotein (PCNA), interleukin (IL)−1β, IL-6, and thromboxane B2 (TxB2) were detected to assess the anti-inflammation and anti-proliferation effects of different treatments. To further study the potential mechanism, TNF-α-induced <i>in vitro</i> model was applied. With different treatments, cell proliferation was detected using MTS, meanwhile, cell cycle distribution and apoptosis were examined by flow cytometric analysis. Western blotting and real-time quantitative PCR were conducted to evaluate many moleculars that involved in interested pathways like COX-2/TxA2 pathway and AKT/FOXO3a pathway. <h3>Results</h3> The paw swelling volume and histological data indicate that 18β-GA administration attenuates arthritis severity in rats with CIA. Lower level of IL-1β, IL-6, and TxB2 were observed in serum of 18β-GA group as compared with model group. In addition, synovial immunohistochemistry data shows that 18β-GA decreased about half of PCNA intensity induced by collagen. However, <i>in vivo</i>, all data exhibited no significant differences among groups with monotherapy and combination therapy. In <i>vitro,</i> 18β-GA inhibited the mRNA and protein levels of COX-2 and TxAS that induced by TNF-α in MH7A cell line. Both p-JNK and NF-κB1 (p50) were inhibited by 18β-GA as well as TxAS siRNA transfection. Moreover, 18β-GA inhibited MH7A proliferation in a time- and dose- dependent manner from MTS assay. Flow cytometric analysis revealed that 18β-GA induced cell apoptosis and caused G1-phase cell cycle arrest. Finally, AKT and FOXO3a were predominantly phosphorylated by TNF-α, whereas such effect was blocked by18β-GA treatment. <h3>Conclusions</h3> This study has for the first time shown that 18β-GA has an inhibitory role in synovial cell inflammation and proliferation, which is, at least in part, dependent on the regulation of COX-2/TxA2pathway and AKT/FOXO3a pathway. Thus,18β-GA should be regarded as a new potential drug candidate for RA therapy. <h3>References</h3> [1] Korczowska I. Rheumatoid arthritis susceptibility genes: An overview. World J Orthop2014;5(4):544–9. [2] Mahmoud AM, et al. Methotrexate hepatotoxicity is associated with oxidative stress, and down-regulation of PPARgamma and Nrf2: Protective effect of 18beta-Glycyrrhetinic acid. Chem Biol Interact2017;270:59–72. <h3>Disclosure of Interest</h3> None declared