Oleanolic acid acetate inhibits rheumatoid arthritis by modulating T cell immune responses and matrix-degrading enzymes

https://doi.org/10.1016/j.taap.2015.11.005Get rights and content

Highlights

  • OAA attenuated chronic CIA symptoms.

  • OAA had a regulating effect on the T helper cell immune reaction for CIA.

  • The effect of OAA on the RA was comparable to the dexamethasone or ketoprofen.

  • OAA might be a candidate for the treatment of arthritic diseases.

ABSTRACT

Rheumatoid arthritis (RA) is a chronic autoimmune disease associated with a combination of synovium joint inflammation, synovium hyperplasia, and destruction of cartilage and bone. Oleanolic acid acetate (OAA), a compound isolated from Vigna angularis, has been known to possess pharmacological activities, including anti-inflammation and anti-bone destruction. In this study, we investigated the effects of OAA on RA and the underlying mechanisms of action by using a type-II collagen-induced arthritis (CIA) mouse model and tumor necrosis factor (TNF)-α-stimulated RA synovial fibroblasts. Oral administration of OAA decreased the clinical arthritis symptoms, paw thickness, histologic and radiologic changes, and serum total and anti-type II collagen IgG, IgG1, and IgG2a levels. OAA administration reduced Th1/Th17 phenotype CD4+ T lymphocyte expansions and inflammatory cytokine productions in T cell activated draining lymph nodes and spleen. OAA reduced the expression and production of inflammatory mediators, such as cytokines and matrix metalloproteinase (MMP)-1/3, in the ankle joint tissue and RA synovial fibroblasts by down-regulating Akt, mitogen-activated protein kinases, and nuclear factor-κB. Our results clearly support that OAA plays a therapeutic role in RA pathogenesis by modulating helper T cell immune responses and matrix-degrading enzymes. The immunosuppressive effects of OAA were comparable to dexamethasone and ketoprofen. We provide evidences that OAA could be a potential therapeutic candidate for RA.

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by changes in synovial inflammation, hyperplasia, erosion, and destruction of cartilage (Nam et al., 2013). The pathogenesis of RA is complex and includes the infiltration of many cell types on articular joints, such as T cells, B cells, macrophages, and synovial fibroblasts (Muller-Ladner et al., 2005). Rheumatoid synovial fibroblasts play a critical role by producing inflammatory cytokines and chemokines that induce the production of matrix metalloproteinases (MMPs) contributing to cartilage and bone destruction (Bartok and Firestein, 2010). Further, T cells initiate the autoimmune process and mediate chronic synovitis, leading to joint destruction (Lubberts, 2014). Thus, RA treatment is directed primarily from minimizing the infiltration of inflammatory cells and preventing joint damage.

Type II collagen-induced arthritis (CIA) mice develop a chronic form of RA and this model closely resembles human RA (Cho et al., 2007). Current approaches to drug therapy for RA include anti-tumor necrosis factors (TNF), interleukin (IL)-1 antagonist drugs, non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying anti-rheumatic drugs (DMARDs) (Asquith et al., 2009, Bevaart et al., 2010). However, the side effects of anti-inflammatory drugs and DMARDs induce significant tissue damage and variety of toxicity.

Recent studies demonstrated that natural products have been used to determine the safe and potential efficacious treatment for RA. Vigna angularis (adzuki bean) is one of the most important crops in Asia and has been widely cultivated in Korea, China, Japan, and Taiwan. V. angularis has a variety of biological actions, including infection, edema, and inflammation of the appendix, kidney, and bladder (Itoh et al., 2005). In addition, oral administration of ethanol extract of V. angularis showed a therapeutic effect on CIA mice (Oh et al., 2014). Oleanolic acid acetate (OAA), a compound isolated from V. angularis, possesses pharmacological activities, such as anti-inflammation and anti-allergy (Oh et al., 2014). We previously reported that oral administration of OAA derived from V. angularis inhibited atopic dermatitis and allergic contact dermatitis in mice (Choi et al., 2013). OAA also inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis through the PLCγ2–Ca2+–NFATc1 pathway, and suppressed inflammatory bone erosion in mice (Kim et al., 2014). However, the effect of OAA on RA has not been studied yet. The objective of this study was to elucidate the therapeutic efficacy of OAA using a CIA mouse model and identify the underlying mechanisms of action.

Section snippets

Purification of OAA from V. angularis

OAA was purified from V. angularis as previously described (Oh et al., 2014). The air-dried and pulverized V. angularis (20 kg) was extracted twice with 95% EtOH at 70 °C. The residue (100 L) was filtered, and then evaporated in a rotary evaporator to yield 95% EtOH extract (2.2 kg). All extract was suspended with distilled water, and sequentially fractionated with EtOAc, n-BuOH, and distilled water. For the isolation of compound, the EtOAc extract was further chromatographed on a silica gel column

OAA suppressed the development of CIA

To evaluate the anti-arthritic effects of OAA, we used CIA mice models treated with an oral administration of OAA (2, 10 or 50 mg/kg) from 28 to 53 days after the initial immunization. The experimental schedules of CIA are shown in Supplementary Fig. S1. The onset of arthritis was monitored until day 56. The known drugs for RA, dexamethasone and ketoprofen, were used as positive controls for treating arthritis pain and inflammation. The paws were appraised for clinical symptoms of arthritis. OAA

Discussion

Oleanolic acid (OA) is a triterpenoid with many beneficial effects. Triterpenoid compounds such as oleanolic acid (OA), ursolic acid, and rosmarinic acid improve inflammation and ulcers in arthritis (Baek et al., 2014, Kapil and Sharma, 1995, Youn et al., 2003). OAA, a derivative of OA and a triterpenoid compound, is known to have therapeutic effects, including atopic dermatitis, allergic contact dermatitis, and inflammatory bone loss in vivo (Choi et al., 2013, Dai et al., 1989, Giner-Larza et

Conflict of interest

The authors have declared no conflict of interest.

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Acknowledgments

This work was supported by the National Research Foundation of Korea Grant funded by the Korean Government (2014R1A5A2009242 and 2012M3A9B6055416), KRIBB Research Initiative Program, and by High Value-added Food Technology Development Program, Ministry of Agriculture, Food and Rural Affairs.

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