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Histone Demethylation and Toll-like Receptor 8-Dependent Cross-Talk in Monocytes Promotes Transdifferentiation of Fibroblasts in Systemic Sclerosis Via Fra-2

Lookup NU author(s): Dr Marzena Ciechomska, Dr Steven O'Reilly, Professor Fiona OakleyORCiD, Professor Jaap van Laar

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Abstract

Objective. To investigate whether epigenetic changes can modulate monocytes to produce tissue inhibitor of metalloproteinases 1 (TIMP-1) via Fra-2 (an activator protein 1 [AP-1] family member), a novel downstream mediator that promotes fibrogenesis.Methods. AP-1 transcription factors and TIMP-1 expression were measured in monocytes from systemic sclerosis (SSc) patients and healthy controls. Involvement of Fra-2 in the regulation of TIMP-1 following treatment with Toll-like receptor 8 (TLR-8) agonist was investigated using a luciferase activity assay and chromatin immunoprecipita-tion (ChIP) analysis. Expression of TIMP-1 and Fra-2 was determined in response to TLR-8 treatment and to different histone modifications, including 3'-deazaneplanocin (DZNep) and apicidin. Fibroblasts from healthy controls were cocultured with DZNep plus TLR-8-treated healthy controlmonocytes.Results. Up-regulation of Fra-2 was detected in bleomycin-challenged mice and in skin biopsy samples from SSc patients. Enhanced expression of Fra-2 and TIMP-1 was correlated in SScmonocytes (P=0.021). The expression of Fra-1 was significantly reduced (P=0.037) in SSc monocytes. Inhibiting AP-1 activity reduced TIMP-1 production in TLR-8-stimulatedmonocytes from healthy controls and SSc patients. ChIP experiments revealed binding of Fra-2 to the TIMP-1 promoter. Stimulation with DZNep plus TLR-8 enhanced Fra-2 and TIMP-1 expression in healthy control monocytes, whereas TLR8 plus apicidin repressed Fra-2 and TIMP-1 expression. Finally, healthy control monocytes treated with DZNep plus TLR-8 induced strong production ofa-smoothmuscle actin in dermal fibroblasts, which was inhibited by TIMP-1-blocking antibody.Conclusion. These data demonstrate a novel role of histone demethylation induced by DZNep on Fra-2-mediated TIMP-1 production by monocytes in the presence of TLR-8 agonist. This consequently orchestrates the transdifferentiation of fibroblasts, a key event in the pathogenesis of SSc.

Publication metadata

Author(s): Ciechomska M, O'Reilly S, Przyborski S, Oakley F, Bogunia-Kubik K, van Laar JM

Publication type: Article

Publication status: Published

Journal: Arthritis & Rheumatology

Year: 2016

Volume: 68

Issue: 6

Pages: 1493-1504

Print publication date: 01/06/2016

Online publication date: 27/01/2016

Acceptance date: 14/01/2016

ISSN (print): 2326-5191

ISSN (electronic): 2326-5205

Publisher: Wiley-Blackwell

URL: http://dx.doi.org/10.1002/art.39602

DOI: 10.1002/art.39602

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