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Oridonin Inhibits Cell Proliferation and Induces Apoptosis in Rheumatoid Arthritis Fibroblast-Like Synoviocytes

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Abstract

Oridonin, an active diterpenoid compound from Rabdosia rubescens, has anti-tumor effects. Rheumatoid arthritis fibroblast-like synoviocytes (RAFLS), a pathological hallmark of RA, exhibits “tumor-like” phenotype. Here, we investigated the effects of oridonin on the proliferation and apoptosis of RAFLS. Cell viability was measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. Apoptosis and mitochondrial membrane potential were detected by flow cytometry. Western blot analysis was performed to examine the phosphorylation of extra-cellular regulated kinases (ERK1/2), C-Jun N-Terminal Kinase (JNK), and p38 mitogen-activated protein kinases and the expression of apoptosis-related proteins. Oridonin inhibited cell proliferation and induced cell apoptosis in interleukin-1β (IL-1β)-treated FLS. z-VAD-fmk, a pan-caspase inhibitor, significantly (P < 0.05) attenuated oridonin-induced apoptosis of FLS. Oridonin suppressed IL-1β-mediated phosphorylation of ERK1/2 and JNK in a dose-dependent manner. Meanwhile, oridonin alone dose-dependently suppressed FLS proliferation, triggered cell apoptosis, and reduced mitochondrial membrane potential (ΔΨm) through activating caspase-3, caspase-9, and PARP, leading to translocation of cytochrome c into cytoplasm. z-VAD-fmk significantly (P < 0.05) inhibited oridonin-induced apoptosis. The accumulation of cellular reactive oxygen species (ROS) was about sevenfold increase in oridonin-treated cells. Pretreatment of N-acetylcysteine (NAC), an inhibitor of ROS, significantly attenuated oridonin-triggered apoptosis, indicating the involvement of ROS production in oridonin-induced mitochondrial apoptosis. Oridonin inhibits cell proliferation, induces cell apoptosis, and decreases the phosphorylation of ERK1/2 and JNK in IL-1β-exposed RAFLS. Oridonin induces mitochondrial apoptosis by enhancing the production of ROS in FLS.

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Authors and Affiliations

  1. Department of Pharmacy, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, 450014, China

    Cai-hong Shang, Qing-qing Zhang & Jian-hua Zhou

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  1. Cai-hong Shang
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  2. Qing-qing Zhang
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  3. Jian-hua Zhou
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Correspondence to Cai-hong Shang.

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Shang, Ch., Zhang, Qq. & Zhou, Jh. Oridonin Inhibits Cell Proliferation and Induces Apoptosis in Rheumatoid Arthritis Fibroblast-Like Synoviocytes. Inflammation 39, 873–880 (2016). https://doi.org/10.1007/s10753-016-0318-2

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