Immunosuppressive Effect of Geniposide on Mitogen-Activated Protein Kinase Signalling Pathway and Their Cross-Talk in Fibroblast-Like Synoviocytes of Adjuvant Arthritis Rats.

Xiang Zhan,Jun Fu,Li Dai,Xuejing Dai,Ran Deng,Hong Wu,Wenyu Wang,Zhengrong Zhang,Feng Li,Yan Wang,Miaomiao Dai

doi:10.3390/molecules23010091

Abstract

Geniposide (GE), an iridoid glycoside compound derived from Gardenia jasminoides Ellis fruit, is known to have anti-inflammatory and immunoregulatory activities. The aim of this study was to investigate the protective mechanism of GE in the regulation of the mitogen-activated protein kinase (MAPK) signalling pathway and the cross-talk among the MAPK signalling pathway in fibroblast-like synoviocytes (FLS) of adjuvant arthritis (AA) rats. AA was induced by injecting with Freund’s complete adjuvant. Male SD rats and FLS were subjected to treatment with GE (30, 60 and 120 mg/kg) in vivo from day 14 to 21 after immunization and GE (25, 50 and 100 μg/mL) in vitro, respectively. The proliferation of FLS was assessed by MTT. IL-4, IL-17, IFN-γ, and TGF-β1 were determined by ELISA. Key proteins in the MAPK signalling pathway were detected by Western blot. GE significantly reduced the proliferation of FLS, along with decreased IFN-γ and IL-17 and increased IL-4 and TGF-β1. In addition, GE decreased the expression of p-JNK, p-ERK1/2 and p-p38 in FLS of AA rats. Furthermore, disrupting one MAPK pathway inhibited the activation of other MAPK pathways, suggesting cross-talk among MAPK signalling. In vivo study, it was also observed that GE attenuated histopathologic changes in the synovial tissue of AA rats. Collectively, the mechanisms by which GE exerts anti-inflammatory and immunoregulatory effects may be related to the synergistic effect of JNK, ERK1/2 and p38. Targeting MAPK signalling may be a new therapeutic strategy in inflammatory/autoimmune diseases.

Highlights

Rheumatoid arthritis (RA) is a chronic, inflammatory, and systemic autoimmune disease, which is characterized by symmetric joint swelling and impaired small diarthrodial joints of the hands and feet [1,2]
120 mg/kg) apparently suppressed the hind paw swelling and polyarthritis index from day 14 to day 21 after immunization (p < 0.01), while there was no significant reduction in polyarthritis index by treatment with GE at 30 mg/kg (p > 0.05)
These results indicated that GE could alleviate the degree of secondary inflammatory response in adjuvant arthritis (AA) rats with Freund’s complete complete adjuvant adjuvant (FCA)-induced injury

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic, inflammatory, and systemic autoimmune disease, which is characterized by symmetric joint swelling and impaired small diarthrodial joints of the hands and feet [1,2]. One report has demonstrated that GE exhibited a protective effect on inflammation in lipopolysaccharide (LPS)-induced primary mouse macrophages in vitro by blocking the phosphorylation of p38MAPK, ERK1/2, JNK, and inhibiting the secretion of TNF-α, IL-1β, and IL-6 [8]. Another study showed that GE inhibited the production of IL-6 and IL-8 in LPS-stimulated human umbilical vein endothelial cells by blocking p38MAPK and ERK1/2 pathways to exhibit anti-inflammatory and immunomodulatory effects [9]. These results suggested that the anti-inflammatory and immune activity of GE is closely related to MAPKs signalling. Therapeutic approaches aimed at modulating MAPKs signalling may have potential therapeutic advantages for inflammatory diseases

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