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TNFR1 and TNFR2 differentially mediate TNF‐α‐induced inflammatory responses in rheumatoid arthritis fibroblast‐like synoviocytes
Author(s) -
Zhang Hongfeng,
Xiao Weiguo
Publication year - 2017
Publication title -
cell biology international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.932
H-Index - 77
eISSN - 1095-8355
pISSN - 1065-6995
DOI - 10.1002/cbin.10735
Subject(s) - tumor necrosis factor alpha , downregulation and upregulation , autocrine signalling , cytokine , gene knockdown , tumor necrosis factor receptor 1 , rheumatoid arthritis , gene silencing , small interfering rna , arthritis , stimulation , fibroblast , chemistry , immunology , proinflammatory cytokine , apoptosis , receptor , cancer research , inflammation , microbiology and biotechnology , medicine , in vitro , transfection , biology , endocrinology , biochemistry , tumor necrosis factor receptor , gene
TNF‐α has long been implicated in the progression of rheumatoid arthritis (RA). However, how the receptors of TNF‐α, namely TNFR1 and TNFR2, mediate TNF‐α‐induced inflammatory responses in fibroblast‐like synoviocytes (FLS) in RA has not been elucidated. In the present study, primary FLS cells were isolated from RA patients and treated with TNF‐α in vitro. The exogenous TNF‐α induced the expression and release of endogenous TNF‐α in FLS. In addition, TNF‐α led to gradual downregulation of TNFR1 following 1 h treatment. By contrast, the expression of TNFR2 was markedly upregulated after 12 h treatment with TNF‐α. Moreover, following TNF‐α treatment, the expression of interleukin (IL)‐2, IL‐6, and IL‐8 was gradually increased with time, but their mRNA levels dropped significantly at 48 h. We further investigated the differential functions of TNFR1 and TNFR2 in FLS by conducting siRNA‐mediated knockdown. The TNF‐α autocrine was inhibited to a greater extent in TNFR1‐silenced FLS compared with TNFR2‐silenced FLS. Silencing of TNFR1, not TNFR2, activated intrinsic apoptosis and inhibited TNF‐α‐induced cytokine production in FLS. These results suggest that TNFR1 is the major pro‐inflammatory mediator of TNF‐α in FLS, whereas TNFR2, which is upregulated in response to prolonged TNF‐α stimulation, may act as an immunosuppressor in FLS for the prevention of overwhelming inflammatory reactions.