Histone Methylation and STAT-3 Differentially Regulate Interleukin-6-Induced Matrix Metalloproteinase Gene Activation in Rheumatoid Arthritis Synovial Fibroblasts.

Autor:	Araki, Yasuto, Tsuzuki Wada, Takuma, Aizaki, Yoshimi, Sato, Kojiro, Yokota, Kazuhiro, Fujimoto, Kenta, Kim, Yoon‐Taek, Oda, Hiromi, Kurokawa, Riki, Mimura, Toshihide
Předmět:	ACADEMIC medical centers ENZYME-linked immunosorbent assay FIBROBLASTS FLOW cytometry GENE expression HISTONES INTERLEUKINS METHYLATION POLYMERASE chain reaction RESEARCH funding RHEUMATOID arthritis STATISTICS SYNOVIAL membranes WESTERN immunoblotting DATA analysis DATA analysis software OLIGONUCLEOTIDE arrays DESCRIPTIVE statistics MATRIX metalloproteinases IN vitro studies MANN Whitney U Test
Zdroj:	Arthritis & Rheumatology; May2016, Vol. 68 Issue 5, p1111-1123, 13p
Abstrakt:	Objective Synovial fibroblasts (SFs) produce matrix-degrading enzymes that cause joint destruction in rheumatoid arthritis (RA). Epigenetic mechanisms play a pivotal role in autoimmune diseases. This study was undertaken to elucidate the epigenetic mechanism that regulates the transcription of matrix metalloproteinases (MMPs) in RASFs. Methods MMP gene expression and histone methylation profiles in the MMP promoters were examined in RASFs. The effect of WD repeat domain 5 ( WDR5) silencing on histone methylation and MMP gene expression in RASFs was analyzed. MMP gene expression, surface expression of the interleukin-6 (IL-6) receptor, phosphorylation of STAT-3, and binding of STAT-3 in the MMP promoters were investigated in RASFs stimulated with IL-6. Results The MMP-1, MMP-3, MMP-9, and MMP-13 genes were actively transcribed in RASFs. Correspondingly, the level of histone H3 trimethylated at lysine 4 (H3K4me3) was elevated, whereas that of H3K27me3 was suppressed in the MMP promoters in RASFs. The decrease in H3K4me3 via WDR5 small interfering RNA reduced the levels of messenger RNA for MMP-1, MMP-3, MMP-9, and MMP-13 in RASFs. Interestingly, IL-6 signaling significantly increased the expression of MMP-1, MMP-3, and MMP-13, but not MMP-9, in RASFs. Although the IL-6 signaling pathway was similarly active in RASFs and osteoarthritis SFs, STAT-3 bound to the MMP-1, MMP-3, and MMP-13 promoters, but not the MMP-9 promoter, after IL-6 stimulation in RASFs. Conclusion Our findings indicate that histone methylation and STAT-3 regulate spontaneous and IL-6-induced MMP gene activation in RASFs. The combination of chromatin structure and transcription factors may regulate distinct arthritogenic properties of RASFs. [ABSTRACT FROM AUTHOR]
Databáze:	Complementary Index
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