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

Siebert, S. , Amos, N., Fielding, C. A., Wang, E. C. Y., Aksentijevich, I., Williams, B. D. and Brennan, P. (2005) Reduced tumor necrosis factor signaling in primary human fibroblasts containing a tumor necrosis factor receptor superfamily 1A mutant. Arthritis and Rheumatism, 52(4), pp. 1287-1292. (doi:10.1002/art.20955) (PMID:15818692) (PMCID:PMC2842000)

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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 α (TNFα)–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-κB 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. TNFα-induced activation of NF-κB 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 TNFα. However, TNFα-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 TNFα-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 TNFα-induced apoptosis.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Siebert, Dr Stefan
Authors: Siebert, S., Amos, N., Fielding, C. A., Wang, E. C. Y., Aksentijevich, I., Williams, B. D., and Brennan, P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Arthritis and Rheumatism
Publisher:John Wiley & Sons, Inc.
ISSN:0004-3591
ISSN (Online):1529-0131

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