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MLL3 Inhibits Apoptosis of Rheumatoid Arthritis Fibroblast-Like Synoviocytes and Promotes Secretion of Inflammatory Factors by Activating CCL2 and the NF-κB Pathway

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Abstract

Rheumatoid arthritis (RA) remains the most common inflammatory arthritis and a major cause of disability. This study investigated the mechanism of MLL3 in fibroblast-like synoviocyte (FLS) apoptosis and inflammatory factor secretion in RA. Expression of MLL3 in synovial tissue of RA patients and patients with bone trauma was detected. FLS was isolated and identified by flow cytometry. Expressions of TNF-α, IL-1β, IL-8, and IL-10 and apoptosis were measured by MTT, flow cytometry, and ELISA. Western blot and qRT-PCR were performed to detect MLL3 and CCL2 expressions, H3K4me3 level, and NF-κB pathway-related proteins in rat joints. MLL3 was highly expressed in the synovial tissue of RA patients, and silencing MLL3 in FLS-RA promoted apoptosis, inhibited pro-inflammatory factors TNF-α, IL-1β, and IL-8 secretion, and promoted anti-inflammatory factor IL-10 secretion. Inhibition of MLL3 suppressed intracellular H3K4me3 and CCL2 expressions. CCL2 activated the NF-κB pathway to promote pro-inflammatory factors TNF-α, IL-1β, and IL-8, inhibit anti-inflammatory factor IL-10, and inhibit apoptosis in FLS-RA. Inhibition of MLL3 expression in RA rats reduced joint redness, swelling, and intra-articular inflammation, but increasing H3K4me3 level reversed the ameliorative effects of sh-MLL3 on RA rats. Collectively, MLL3 activated the NF-κB pathway by increasing H3K4me3 modification in the CCL2 promoter region in FLS-RA, thereby inhibiting apoptosis and promoting pro-inflammatory factors of FLS-RA.

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Data availability

The datasets and materials used during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank all the members in our team for the excellent work.

Funding

This research was supported by funds from the 2019 Xinxiang City Science and Technology Research Plan Project(GG2019026); The Henan Medical Science and Technology Public Relations Plan jointly established a project(LHGJ20200959, LHGJ20200941).

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Authors and Affiliations

  1. Department of Rheumatology and Immunology, Xinxiang Central Hospital, NO.56 Jinsui Avenue, Xinxiang, 453000, Henan, China

    Wenqiang Fan, Zhendan Xu, Shu Liang, Shufei Zuo, Caiyue Bian, Xiao Gao, Yilu Qin & Jie Wu

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  1. Wenqiang Fan
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Contributions

Conceptualization: WF and SL. Validation, research, resources, data reviewing, and writing: ZX, AZ, and ZB. Review and editing: XG, YQ, and JW. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Jie Wu.

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Ethics Approval and Consent to Participate

This study obtained approval from the ethics committee of Xinxiang Central Hospital, and all procedures were conducted according to the declaration of Helsinki. The animal experiments were performed with the principle of minimized animal number and the least pains.

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Informed consents were signed by each enrolled patients.

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The authors declare no competing interests.

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Fan, W., Xu, Z., Liang, S. et al. MLL3 Inhibits Apoptosis of Rheumatoid Arthritis Fibroblast-Like Synoviocytes and Promotes Secretion of Inflammatory Factors by Activating CCL2 and the NF-κB Pathway. Inflammation 44, 1803–1814 (2021). https://doi.org/10.1007/s10753-021-01459-2

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  • DOI: https://doi.org/10.1007/s10753-021-01459-2

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