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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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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


DOI: 10.1002/art.39602


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Funder referenceFunder name
European Union Structural Funds
JGW Patterson Foundation
NIHR Newcastle Biomedical Research Centre at Newcastle Hospitals Foundation Trust
NIHR Newcastle Biomedical Research Centre at Newcastle University
Eli Lilly
Wroclaw Centre of Biotechnology (Leading National Research Centre [KNOW] program)
2013-8/4Foundation for Polish Science (Homing Plus grant)