Tumor necrosis factor receptor I blockade shows that TNF-dependent and independent mechanisms synergise in TNF receptor associated periodic syndrome

Fairclough, Lucy C. and Stoop, A.A. and Negm, Ola H. and Radford, Paul and Tighe, Patrick J. and Todd, Ian (2015) Tumor necrosis factor receptor I blockade shows that TNF-dependent and independent mechanisms synergise in TNF receptor associated periodic syndrome. European Journal of Immunology, 45 (10). pp. 2937-2944. ISSN 1521-4141

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Abstract

TNF receptor associated periodic syndrome (TRAPS) is an autoinflammatory disease involving recurrent episodes of fever and inflammation. It is associated with autosomal dominant mutations in TNF receptor superfamily 1A gene localised to exons encoding the ectodomain of the p55 TNF receptor, TNF receptor-1 (TNFR1). The aim of this study was to investigate the role of cell surface TNFR1 in TRAPS, and the contribution of TNF-dependent and TNF-independent mechanisms to the production of cytokines. HEK-293 and SK-HEP-1 cell lines were stably transfected with WT or TRAPS-associated variants of human TNF receptor superfamily 1A gene. An anti-TNFR1 single domain antibody (dAb), and an anti-TNFR1 mAb, bound to cell surface WT and variant TNFR1s. In HEK-293 cells transfected with death domain-inactivated (R347A) TNFR1, and in SK-HEP-1 cells transfected with normal (full-length) TNFR1, cytokine production stimulated in the absence of exogenous TNF by the presence of certain TNFR1 variants was not inhibited by the anti-TNFR1 dAb. In SK-Hep-1 cells, specific TRAPS mutations increased the level of cytokine response to TNF, compared to WT, and this augmented cytokine production was suppressed by the anti-TNFR1 dAb. Thus, TRAPS-associated variants of TNFR1 enhance cytokine production by a TNF-independent mechanism and by sensitising cells to a TNF-dependent stimulation. The TNF-dependent mechanism requires cell surface expression of TNFR1, as this is blocked by TNFR1-specific dAb.

Item Type: Article
Additional Information: This is the peer reviewed version of the following article: Fairclough, L. C., Stoop, A. A., Negm, O. H., Radford, P. M., Tighe, P. J. and Todd, I. (2015), Tumour necrosis factor receptor I blockade shows that TNF-dependent and TNF-independent mechanisms synergise in TNF receptor associated periodic syndrome. Eur. J. Immunol., 45: 2937–2944. doi: 10.1002/eji.201545769, which has been published in final form at http://dx.doi.org/10.1002/eji.201545769. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Life Sciences
Identification Number: https://doi.org/10.1002/eji.201545769
Depositing User: Fairclough, Lucy
Date Deposited: 22 Feb 2017 08:15
Last Modified: 22 Feb 2017 19:54
URI: http://eprints.nottingham.ac.uk/id/eprint/40681

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