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

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.

• Authors: Wenqiang Fan, Zhendan Xu, Shu Liang, Shufei Zuo, Caiyue Bian, Xiao Gao, Yilu Qin, Jie Wu
• Journal: Inflammation (Inflammation) Vol. 44 Issue 5 Pg. 1803-1814 (Oct 2021) ISSN: 1573-2576 [Electronic] United States
• PMID: 33914205 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Chemical References

• Anti-Inflammatory Agents
• CCL2 protein, human
• Chemokine CCL2
• DNA-Binding Proteins
• Inflammation Mediators
• KMT2C protein, human
• NF-kappa B

Topics

• Adult
• Aged
• Animals
• Anti-Inflammatory Agents
• Apoptosis (physiology)
• Arthritis, Rheumatoid (genetics, metabolism, pathology)
• Chemokine CCL2 (metabolism)
• DNA-Binding Proteins (biosynthesis, genetics)
• Female
• Fibroblasts (metabolism, pathology)
• Humans
• Inflammation Mediators (metabolism)
• Male
• Middle Aged
• NF-kappa B (metabolism)
• Rats
• Rats, Sprague-Dawley
• Synoviocytes (metabolism, pathology)