Reduced tumor necrosis factor signaling in primary human fibroblasts containing a tumor necrosis factor receptor superfamily 1A mutant

Siebert, Stefan, Amos, Nick, Fielding, Ceri Alan ORCID: https://orcid.org/0000-0002-5817-3153, Wang, Edward Chung Yern ORCID: https://orcid.org/0000-0002-2243-4964, Aksentijevich, Ivona, Williams, Bryan Davies and Brennan, Paul ORCID: https://orcid.org/0000-0001-8792-0499 2005. Reduced tumor necrosis factor signaling in primary human fibroblasts containing a tumor necrosis factor receptor superfamily 1A mutant. Arthritis & Rheumatism 52 (4) , pp. 1287-1282. 10.1002/art.20955

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Abstract

Objective Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autoinflammatory syndrome associated with mutations in the gene that encodes tumor necrosis factor receptor superfamily 1A (TNFRSF1A). The purpose of this study was to describe a novel TNFRSF1A mutation (C43S) in a patient with TRAPS and to examine the effects of this TNFRSF1A mutation on tumor necrosis factor (TNF)-induced signaling in a patient-derived primary dermal fibroblast line. Methods TNFRSF1A shedding from neutrophils was measured by flow cytometry and enzyme-linked immunosorbent assay (ELISA). Primary dermal fibroblast lines were established from the patient with the C43S TRAPS mutation and from healthy volunteers. Activation of NF-B and activator protein 1 (AP-1) was evaluated by electrophoretic mobility shift assays. Cytokine production was measured by ELISA. Cell viability was measured by alamar blue assay. Apoptosis was measured by caspase 3 assay in the fibroblasts and by annexin V assay in peripheral blood mononuclear cells. Results Activation-induced shedding of the TNFRSF1A from neutrophils was not altered by the C43S TRAPS mutation. TNF-induced activation of NF-B and AP-1 was decreased in the primary dermal fibroblasts with the C43S TNFRSF1A mutation. Nevertheless, the C43S TRAPS fibroblasts were capable of producing interleukin-6 (IL-6) and IL-8 in response to TNF. However, TNF-induced cell death and apoptosis were significantly decreased in the samples from the patient with the C43S TRAPS mutation. Conclusion The C43S TNFRSF1A mutation results in decreased TNF-induced nuclear signaling and apoptosis. Our data suggest a new hypothesis, in that the C43S TRAPS mutation may cause the inflammatory phenotype by increasing resistance to TNF-induced apoptosis.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Publisher:	John Wiley & Sons
ISSN:	0004-3591
Last Modified:	17 Oct 2022 08:29
URI:	https://orca.cardiff.ac.uk/id/eprint/293

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