Regulation of Cytokine and Chemokine Expression by Histone Lysine Methyltransferase MLL1 in Rheumatoid Arthritis Synovial Fibroblasts

Overview

Journal Sci Rep

Specialty Science

Date 2024 May 8

PMID 38719857

Authors

Keita Okamoto

Yasuto Araki

Yoshimi Aizaki

Shinya Tanaka

Yuho Kadono

Toshihide Mimura

Affiliations

Soon will be listed here.

Abstract

Histone lysine methylation is thought to play a role in the pathogenesis of rheumatoid arthritis (RA). We previously reported aberrant expression of the gene encoding mixed-lineage leukemia 1 (MLL1), which catalyzes methylation of histone H3 lysine 4 (H3K4), in RA synovial fibroblasts (SFs). The aim of this study was to elucidate the involvement of MLL1 in the activated phenotype of RASFs. SFs were isolated from synovial tissues obtained from patients with RA or osteoarthritis (OA) during total knee joint replacement. MLL1 mRNA and protein levels were determined after stimulation with tumor necrosis factor α (TNFα). We also examined changes in trimethylation of H3K4 (H3K4me3) levels in the promoters of RA-associated genes (matrix-degrading enzymes, cytokines, and chemokines) and the mRNA levels upon small interfering RNA-mediated depletion of MLL1 in RASFs. We then determined the levels of H3K4me3 and mRNAs following treatment with the WD repeat domain 5 (WDR5)/MLL1 inhibitor MM-102. H3K4me3 levels in the gene promoters were also compared between RASFs and OASFs. After TNFα stimulation, MLL1 mRNA and protein levels were higher in RASFs than OASFs. Silencing of MLL1 significantly reduced H3K4me3 levels in the promoters of several cytokine (interleukin-6 [IL-6], IL-15) and chemokine (C-C motif chemokine ligand 2 [CCL2], CCL5, C-X-C motif chemokine ligand 9 [CXCL9], CXCL10, CXCL11, and C-X3-C motif chemokine ligand 1 [CX3CL1]) genes in RASFs. Correspondingly, the mRNA levels of these genes were significantly decreased. MM-102 significantly reduced the promoter H3K4me3 and mRNA levels of the CCL5, CXCL9, CXCL10, and CXCL11 genes in RASFs. In addition, H3K4me3 levels in the promoters of the IL-6, IL-15, CCL2, CCL5, CXCL9, CXCL10, CXCL11, and CX3CL1 genes were significantly higher in RASFs than OASFs. Our findings suggest that MLL1 regulates the expression of particular cytokines and chemokines in RASFs and is associated with the pathogenesis of RA. These results could lead to new therapies for RA.

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References

Karin N, Wildbaum G, Thelen M . Biased signaling pathways via CXCR3 control the development and function of CD4+ T cell subsets. J Leukoc Biol. 2015; 99(6):857-62. DOI: 10.1189/jlb.2MR0915-441R. View

Trenkmann M, Brock M, Gay R, Kolling C, Speich R, Michel B . Expression and function of EZH2 in synovial fibroblasts: epigenetic repression of the Wnt inhibitor SFRP1 in rheumatoid arthritis. Ann Rheum Dis. 2011; 70(8):1482-8. DOI: 10.1136/ard.2010.143040. View

Miranda-Carus M, Balsa A, Benito-Miguel M, Perez de Ayala C, Martin-Mola E . IL-15 and the initiation of cell contact-dependent synovial fibroblast-T lymphocyte cross-talk in rheumatoid arthritis: effect of methotrexate. J Immunol. 2004; 173(2):1463-76. DOI: 10.4049/jimmunol.173.2.1463. View

Benito-Miguel M, Garcia-Carmona Y, Balsa A, Bautista-Caro M, Arroyo-Villa I, Cobo-Ibanez T . IL-15 expression on RA synovial fibroblasts promotes B cell survival. PLoS One. 2012; 7(7):e40620. PMC: 3392224. DOI: 10.1371/journal.pone.0040620. View

Sakkas L, Bogdanos D, Katsiari C, Platsoucas C . Anti-citrullinated peptides as autoantigens in rheumatoid arthritis-relevance to treatment. Autoimmun Rev. 2014; 13(11):1114-20. DOI: 10.1016/j.autrev.2014.08.012. View

Araki Y, Wang Z, Zang C, Wood 3rd W, Schones D, Cui K . Genome-wide analysis of histone methylation reveals chromatin state-based regulation of gene transcription and function of memory CD8+ T cells. Immunity. 2009; 30(6):912-25. PMC: 2709841. DOI: 10.1016/j.immuni.2009.05.006. View

Arnett F, Edworthy S, Bloch D, McShane D, Fries J, Cooper N . The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988; 31(3):315-24. DOI: 10.1002/art.1780310302. View

Araki Y, Fann M, Wersto R, Weng N . Histone acetylation facilitates rapid and robust memory CD8 T cell response through differential expression of effector molecules (eomesodermin and its targets: perforin and granzyme B). J Immunol. 2008; 180(12):8102-8. PMC: 2493419. DOI: 10.4049/jimmunol.180.12.8102. View

Berger S, Kouzarides T, Shiekhattar R, Shilatifard A . An operational definition of epigenetics. Genes Dev. 2009; 23(7):781-3. PMC: 3959995. DOI: 10.1101/gad.1787609. View

10.

Weng N, Araki Y, Subedi K . The molecular basis of the memory T cell response: differential gene expression and its epigenetic regulation. Nat Rev Immunol. 2012; 12(4):306-15. PMC: 4686144. DOI: 10.1038/nri3173. View

11.

Timmer T, Baltus B, Vondenhoff M, Huizinga T, Tak P, Verweij C . Inflammation and ectopic lymphoid structures in rheumatoid arthritis synovial tissues dissected by genomics technology: identification of the interleukin-7 signaling pathway in tissues with lymphoid neogenesis. Arthritis Rheum. 2007; 56(8):2492-502. DOI: 10.1002/art.22748. View

12.

Scacheri P, Davis S, Odom D, Crawford G, Perkins S, Halawi M . Genome-wide analysis of menin binding provides insights into MEN1 tumorigenesis. PLoS Genet. 2006; 2(4):e51. PMC: 1428788. DOI: 10.1371/journal.pgen.0020051. View

13.

Bleul C, Fuhlbrigge R, Casasnovas J, Aiuti A, Springer T . A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1). J Exp Med. 1996; 184(3):1101-9. PMC: 2192798. DOI: 10.1084/jem.184.3.1101. View

14.

Bartok B, Firestein G . Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev. 2010; 233(1):233-55. PMC: 2913689. DOI: 10.1111/j.0105-2896.2009.00859.x. View

15.

Hirano T, Matsuda T, Turner M, Miyasaka N, Buchan G, Tang B . Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis. Eur J Immunol. 1988; 18(11):1797-801. DOI: 10.1002/eji.1830181122. View

16.

Araki Y, Mimura T . Matrix Metalloproteinase Gene Activation Resulting from Disordred Epigenetic Mechanisms in Rheumatoid Arthritis. Int J Mol Sci. 2017; 18(5). PMC: 5454818. DOI: 10.3390/ijms18050905. View

17.

Yu B, Hess J, Horning S, Brown G, Korsmeyer S . Altered Hox expression and segmental identity in Mll-mutant mice. Nature. 1995; 378(6556):505-8. DOI: 10.1038/378505a0. View

18.

Goldberg M, Nadiv O, Luknar-Gabor N, Agar G, Beer Y, Katz Y . Synergism between tumor necrosis factor alpha and interleukin-17 to induce IL-23 p19 expression in fibroblast-like synoviocytes. Mol Immunol. 2009; 46(8-9):1854-9. DOI: 10.1016/j.molimm.2009.01.004. View

19.

Tsubaki T, Takegawa S, Hanamoto H, Arita N, Kamogawa J, Yamamoto H . Accumulation of plasma cells expressing CXCR3 in the synovial sublining regions of early rheumatoid arthritis in association with production of Mig/CXCL9 by synovial fibroblasts. Clin Exp Immunol. 2005; 141(2):363-71. PMC: 1809426. DOI: 10.1111/j.1365-2249.2005.02850.x. View

20.

Araki Y, Tsuzuki Wada T, Aizaki Y, Sato K, Yokota K, Fujimoto K . Histone Methylation and STAT-3 Differentially Regulate Interleukin-6-Induced Matrix Metalloproteinase Gene Activation in Rheumatoid Arthritis Synovial Fibroblasts. Arthritis Rheumatol. 2015; 68(5):1111-23. DOI: 10.1002/art.39563. View