TNFR1 and TNFR2 differentially mediate TNF‐α‐induced inflammatory responses in rheumatoid arthritis fibroblast‐like synoviocytes

Abstract

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.

Interleukin-6 and tumour necrosis factor-α cooperatively promote cell cycle regulators and proliferate rheumatoid arthritis fibroblast-like synovial cells

“…Although RA-FLS contains both TNFR1 and TNFR2 (8), 'death signal' originated from TNFR1 is suppressed (38) and NF-κB signaling pathway is highly activated (7).…”

Aberrant frequency of TNFR2+ Treg and related cytokines in patients with CIN and cervical cancer

“…Meanwhile, we also detected a dramatic increase in the proportion of TNFR2 + Tregs in TILs compared to PB, indicating a recruitment of TNFR2 + Tregs into the tumor microenvironment from the periphery, which possibly contributed to the tumor immune evasion. An elevated level of TNFR2 + Tregs is correlated with highly immunosuppressive microenvironment in malignant diseases, such as acute myeloid leukemia (AML) [ 19 ], lung cancer [ 20 ], and ovarian cancer [ 21 ], as well as in autoimmune disorders including type 1 diabetes and rheumatoid arthritis [ 22 , 23 ]. Ex vivo experiments also demonstrated a novel regulatory role of TNFR2 on Treg cell function and expansion [ 24 – 26 ].…”

Anti‐Inflammatory Effects of p‐Coumaric Acid, a Natural Compound of Oldenlandia diffusa, on Arthritis Model Rats

“…Exterior changes involve joint malformation, swelling, and joint dysfunction [ 3 , 4 ], while interior pathological changes mainly involve synovial hyperplasia and cartilage destruction. All of these changes are accompanied by systemic inflammatory responses [ 5 , 6 ], involving many cytokines, such as TNF- α [ 7 , 8 ] and IL-6 [ 9 – 11 ], which are responsible for initiating, propagating, and maintaining inflammation [ 12 ] in a complex network [ 13 ]. Recent studies have shown that TNF- α governs the crosstalk between fibroblast-like synoviocytes and chondrocytes [ 12 ] and might regulate the expressional changes in matrix-degrading enzymes and inflammatory mediators in fibroblast-like synoviocytes [ 12 ] and induce the inflammatory responses.…”