AB0122 Rp53 induces ectodomain shedding of tnf receptor 1 and thereby inhibits inflammatory responses in rheumatoid fibroblast-like synoviocytes. (12th June 2018)

• Record Type: Journal Article
• Authors: Kim, J.; Byun, H.S.; Kang, K.; Yoo, S.-J.; Kang, S.W.; Hur, G.M.
• Is Part Of: Annals of the rheumatic diseases. Volume 77(2018)Supplement 2
• Page Start: 1255
• Page End: 1255
• Publication Date: 2018-06-12
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2018-eular.5178
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease by autoimmune disorder that primarily affects joints. Usually RA has been treated with disease modifying anti-rheumatic drugs but biological response modifiers has developed the treatment of RA. Among these anti-tumour necrosis factor (TNF) agents were the first to be successfully used in treating RA. Various anti-TNF-α therapy might be lead to substantial functional improvement in RA patients. Objectives: We studied the isolated two polypeptides (Rp53, Rp54) from Rubia philippinensis, traditional medicine plant, about anti-inflammation effects in fibroblast-like synoviocytes (FLS) derived from patients with RA. Methods: The effects of polypeptides on anti-inflammation were measured by cytokine assay kits (TNF-α, IL-6). The underlying for NF-κB signalling pathway was examined by western blot and NF-kB reporter activity. We examined the effect of Rp53 on the formation of the TNFR1 signalling complex, recruitment of TRADD, RIP in response to TNF by immunoprecipitation experiments. To determine whether Rp53 induced TNF receptor 1 shedding were exposed to these compounds for 1 hour, and then culture media and cell lysates were analysed by Western blotting using anti-TNF receptor 1 antibody. Results: Pretreatment with Rp53 resulted in a remarkable decrease of the secretion of TNF-induced proinflammatory cytokines TNF-α and IL-6 in RA–FLS. Rp53 strongly inhibited the nuclear factor kB (NF-κB) signalling pathway induced by TNF-α, but not that induced by IL-1β. Analysis of the upstream signalling events affected by Rp53 revealed that it strikingly inhibited the TNF-induced recruitment of TNFR1-associated death domain protein (TRADD) and receptor-interacting protein (RIP) to TNFR1. Rp53 reduced the interaction with TNFR1 to TNF cytokines and enhanced the activation of the p38 mitogen-activated protein (MAP) kinase. Rp53, the polypeptides induced the proteolytic cleavage of TNF-R1 and its release into the culture medium by shedding of TNF receptor 1 ectodomain by TNF-α-converting enzyme (TACE). Along with the TACE inhibitor TAPI-2, the p38 kinase inhibitor SB203580 suppressed the ectodomain shedding of TNF receptor 1 induced by Rp53. Conclusions: Rp53 induces the TACE-dependent ectodomain shedding of TNF receptor 1 through the activation of p38 MAP kinase, and thereby inhibits the TNF-α induced NF-κB signalling pathway in RA-FLS cells. Disclosure of Interest: None declared