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Arthritis Res Ther. 2017 Dec 1;19(1):263. doi: 10.1186/s13075-017-1472-0.

Resistin upregulates chemokine production by fibroblast-like synoviocytes from patients with rheumatoid arthritis.

Author information

1
Department of Internal Medicine, Graduate School of Medicine, Toho University, Tokyo, Japan.
2
Division of Rheumatology, Department of Internal Medicine, Toho University School of Medicine, 6-11-1 Omori-Nishi, Ota-ku, Tokyo, 143-8541, Japan.
3
KAN Research Institute Inc, 6-8-2 Minatojima-minamimachi, Chuo-Ku, Kobe, 650-0047, Japan.
4
Unit of Regenerative Diseases Research, Division of Research Promotion and Development, Advanced Medical Research Center, Toho University Graduate School of Medicine, Tokyo, Japan.
5
Department of Surgical Pathology, Toho University School of Medicine, Tokyo, Japan.
6
Department of Orthopedic Surgery, Toho University School of Medicine, Tokyo, Japan.
7
Department of Inflammation and Pain Control Research, Toho University School of Medicine, Tokyo, Japan.
8
Department of Internal Medicine, Graduate School of Medicine, Toho University, Tokyo, Japan. toshihiro.nanki@med.toho-u.ac.jp.
9
Division of Rheumatology, Department of Internal Medicine, Toho University School of Medicine, 6-11-1 Omori-Nishi, Ota-ku, Tokyo, 143-8541, Japan. toshihiro.nanki@med.toho-u.ac.jp.

Abstract

BACKGROUND:

Adipokines are bioactive hormones secreted by adipose tissues. Resistin, an adipokine, plays important roles in the regulation of insulin resistance and inflammation. Resistin levels are known to be increased in the serum and synovial fluid of rheumatoid arthritis (RA) patients. However, the pathogenic role of resistin in RA has not yet been elucidated.

METHODS:

The expression of resistin and adenylate cyclase-associated protein 1 (CAP1), a receptor for resistin, was examined immunohistochemically in synovial tissue. CAP1 expression in in vitro cultured fibroblast-like synoviocytes (FLSs) was assessed with a reverse transcription-polymerase chain reaction (PCR) and western blotting. The gene expression of resistin-stimulated FLSs was evaluated by RNA sequencing (RNA-Seq) and quantitative real-time PCR. Concentrations of chemokine (C-X-C motif) ligand (CXCL) 8, chemokine (C-C motif) ligand (CCL) 2, interleukin (IL)-1β, IL-6 and IL-32 in culture supernatants were measured by enzyme-linked immunosorbent assay. Small interfering RNA (siRNA) for CAP1 was transfected into FLSs in order to examine inhibitory effects.

RESULTS:

The expression of resistin and CAP1 in synovial tissue was stronger in RA than in osteoarthritis (OA). Resistin was expressed by macrophages in the RA synovium, while CAP1 was expressed by macrophages, FLSs and endothelial cells. In vitro cultured RA FLSs also expressed CAP1. RNA-Seq revealed that the expression levels of 18 molecules were more than twofold higher in resistin-stimulated FLSs than in unstimulated FLSs. Seven chemokines, CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL8, and CCL2, were included among the 18 molecules. Increases induced in the expression of CXCL1, CXCL8, and CCL2 by the resistin stimulation were confirmed by real-time PCR. The stimulation with resistin increased the protein levels of CXCL8 and CCL2 produced by RA FLSs, and the upregulated expression of CXCL8 was inhibited by the abrogation of CAP1 by siRNA for CAP1. Production of IL-6 by FLSs was also increased by resistin. Expression of IL-1β and IL-32 was not detected by ELISA.

CONCLUSIONS:

Resistin contributes to the pathogenesis of RA by increasing chemokine production by FLSs via CAP1 in synovial tissue.

KEYWORDS:

Adenylate cyclase-associated protein 1; Chemokine; Fibroblast-like synoviocytes; RNA sequencing; Resistin; Rheumatoid arthritis

PMID:
29191223
PMCID:
PMC5709830
DOI:
10.1186/s13075-017-1472-0
[Indexed for MEDLINE]
Free PMC Article

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