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Genistein Inhibit Cytokines or Growth Factor-Induced Proliferation and Transformation Phenotype in Fibroblast-Like Synoviocytes of Rheumatoid Arthritis

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Abstract

The purpose of this research is to study the effect of genistein on cytokines or growth factor-induced proliferation and transformation phenotype of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS). RA-FLS were primarily cultured. With respective stimulation of IL-1β, TNF-α, and EGF, genistein was applied to elucidate its effect on synoviocytes’ growth number, cell proliferation assay, cell cycle using cell counts, 3H-TdR incorporation and flow cytometry, the colony numbers under anchorage-independent condition, and the expression of MMP-2 and MMP-9 in synovial fibroblasts. EGF, IL-1β, and TNF-α increased 3H incorporation in RA-FLS, respectively. EGF augmented clone numbers of RA-FLS under anchorage-independent condition and not IL-1β and TNF-α. Genistein had an inhibitory role on cell number and 3H-TdR incorporation of RA-FLS stimulated with IL-1β, TNF-α and EGF; genistein arrested the cell cycle at G1 restriction point; genistein decreased colony numbers under anchorage-independent condition stimulated by EGF in serum condition. IL-1β or TNF-α increased expression of MMP-9 and MMP-2 in rheumatoid synoviocytes; EGF stimulated expression of MMP-9 but not of MMP-2; genistein suppressed production of MMP-9 more than MMP-2 induced by IL-1β or TNF-α; rMMP-9, rMMP-2, or their inhibitors had no effect on the 3H-TdR incorporation of synovial cells. Erk1/2 inhibitor (PD098 059) had obvious inhibitory effect on the 3H incorporation induced by TNF-α or IL-1β; inhibitors of JNK (SP600 125) had no significant effect on the 3H incorporation. While pretreatment with PD098059 had no marked inhibitory effect on MMP-9 expression induced by TNF-α or IL-1β, SP600125 decreased significantly the MMP-9 expression induced by TNF-α or IL-1β. Neither PD098059 nor SP600 125 could inhibit the MMP-2 expression induced by TNF-α or IL-1β. Genistein inhibited IL-1β, TNF-α or EGF-induced proliferation and MMP-9 expression in fibroblast-like synoviocytes of rheumatoid arthritis; the proliferation of RA-FLS was mediated by Erk1/2 but not JNK activation, while JNK activation was involved in the signal transduction pathway leading to MMP-9 expression in rheumatoid synoviocytes.

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Acknowledgment

This work was supported by a grant from the National Natural Science Foundation of China (no. 30801160)

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Authors and Affiliations

  1. Clinical Institute of Molecular Biology, People’s Hospital, Peking University, Beijing, China

    Yujun Zhang, Jianqiang Dong, Peiying He, Qi Zhang & Na Li

  2. Arthritis Clinic and Research Center, People’s Hospital, Peking University, Beijing, 100044, China

    Wende Li & Tiezheng Sun

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  1. Yujun Zhang
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Correspondence to Tiezheng Sun.

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Zhang, Y., Dong, J., He, P. et al. Genistein Inhibit Cytokines or Growth Factor-Induced Proliferation and Transformation Phenotype in Fibroblast-Like Synoviocytes of Rheumatoid Arthritis. Inflammation 35, 377–387 (2012). https://doi.org/10.1007/s10753-011-9365-x

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