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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.

Ciechomska, M. and O'Reilly, S. and Przyborski, S. and Oakley, F. and Bogunia-Kubik, K. and van Laar, J.M. (2016) 'Histone demethylation and toll‐like receptor 8–dependent cross‐talk in monocytes promotes transdifferentiation of fibroblasts in systemic sclerosis via Fra‐2.', Arthritis and rheumatology., 68 (6). pp. 1493-1504.

Abstract

Objectives: To investigate whether epigenetic changes can modulate monocytes to produce tissue-inhibitor of metalloproteinase-1 (TIMP-1) via Fra2 (AP-1 family member), a novel downstream mediator promoting fibrogenesis. Methods: AP-1 transcription factors and TIMP-1 expression was measured in monocytes from systemic sclerosis (SSc) patients and healthy controls (HC). Involvement of Fra2 in the regulation of TIMP-1 following TLR8 agonist treatment was investigated using luciferase activity assay and ChIP analysis. Expression of TIMP-1 and Fra2 was determined in response to TLR8 treatment and different histone modifications including 3'deazaneplanocin (DZNep) and apicidin. HC fibroblasts were co-cultured with DZNep plus TLR8-treated HC monocytes. Results: Upregulation of Fra2 was detected in bleomycin-challenged mice and SSc skin biopsies. Enhanced expression of Fra2 and TIMP-1 was correlated in SSc monocytes (p=0.021). The expression of Fra1 was significantly (p=0.037) reduced in SSc monocytes. Inhibiting AP-1 activity reduced TIMP-1 production in TLR8 stimulated HC and SSc monocytes. ChIP experiments revealed binding of Fra-2 to the TIMP-1 promoter. Combination of DZNep plus TLR8 enhanced Fra2 and TIMP-1 expression in HC monocytes, whereas TLR8 plus apicidin repressed Fra2 and TIMP-1 expression. Finally, DZNep plus TLR8-treated HC monocytes induced strong production of α-SMA in dermal fibroblasts, which was inhibited by TIMP-1 blocking antibody. Conclusions: These data demonstrate a novel role of histone demethylation induced by DZNep on Fra2-mediated TIMP-1 production by monocytes in the presence of TLR8 agonist. This consequently orchestrates fibroblasts' trans-differentiation, a key event in the pathogenesis of SSc.

Item Type:Article
Keywords:Systemic sclerosis, Monocytes, TLR signaling, Epigenetics, TIMP-1.
Full text:(AM) Accepted Manuscript
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Status:Peer-reviewed
Publisher Web site:https://doi.org/10.1002/art.39602
Publisher statement:This is the accepted version of the following article: Ciechomska, M., O'Reilly, S., Przyborski, S., Oakley, F., Bogunia-Kubik, K. & van Laar, J.M. (2016). Histone demethylation and toll‐like receptor 8–dependent cross‐talk in monocytes promotes transdifferentiation of fibroblasts in systemic sclerosis via Fra‐2. Arthritis & Rheumatology 68(6): 1493-1504, which has been published in final form at https://doi.org/10.1002/art.39602. This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving.
Date accepted:14 January 2016
Date deposited:09 February 2016
Date of first online publication:26 May 2016
Date first made open access:26 May 2017

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