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Clin Exp Rheumatol. 2018 Jan-Feb;36(1):62-72. Epub 2017 Jul 6.

Pro-fibrotic effect of IL-6 via aortic adventitial fibroblasts indicates IL-6 as a treatment target in Takayasu arteritis.

Author information

1
Department of Rheumatology, Zhongshan Hospital, Fudan University, Shanghai, China.
2
Department of Vascular Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
3
Department of Pathology, Shanghai Medical College, Fudan University, Shanghai, China.
4
Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.
5
Key Laboratory of Glycoconjugate Research Ministry of Public Health, Gene Research Center, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
6
Department of Rheumatology, Zhongshan Hospital, Fudan University, Shanghai, China. zsh-rheum@hotmail.com.

Abstract

OBJECTIVES:

This study aimed to clarify potential mechanism of IL-6 involved in adventitial fibrosis via adventitial fibroblast in Takayasu arteritis (TAK).

METHODS:

Immunohistochemistry and double-labelled immunofluorescence were performed on vascular tissue from patients with TAK and controls. Human aorta adventitial fibroblast (AAF) was cultured and stimulated with interleukine 6 (IL-6)/IL-6 receptor (IL-6R). Real-time PCR, western blot, enzyme-linked immunosorbent assays, chromatin immunoprecipitation (ChIP) and reporter assay were conducted in vitro experiments to determine effect of IL-6/IL-6R on AAF.

RESULTS:

The expression of IL-6, IL-6R, collagen I, collagen III, fibronectin, α-smooth muscle actin (α-SMA), and transforming growth factor (TGF-β) in TAK arteries was significantly higher than that in the normal arteries. Co-localisation of α-SMA and IL-6 and a positive correlation between their expression were observed in local lesions. In vitro experiments, collagen I, collagen III, fibronectin, α-SMA, and TGF-β expression increased significantly after stimulation and this fibrogenesis of AAFs was induced in TGF-β-dependent and -independent manners. Additionally, phosphorylation of JAK2, STAT3 and Akt was significantly enhanced both in IL-6/IL-6R-treated AAFs in vitro and in TAK adventitial α-SMA positive cells. When AAFs were pretreated with inhibitors against JAK2, STAT3, and Akt, fibrosis was significantly reduced. Furthermore, IL-6/IL-6R promoted mRNA expression of IL-6 and MCP-1 in AAFs. Finally, according to ChIP and reporter assay results, STAT3 was the main transcriptional factor in the fibrosis of AAFs induced by IL-6/IL-6R.

CONCLUSIONS:

IL-6/IL-6R induces fibrogenesis of AAFs via the JAK2/STAT3 and JAK2/Akt pathways, which provides theoretical evidence for IL-6 as a treatment target in TAK.

PMID:
28770707
[Indexed for MEDLINE]

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