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A pro-inflammatory signalome is constitutively activated by C33Y mutant TNF receptor 1 in TNF receptor-associated periodic syndrome (TRAPS)

Negm, Ola H.; Mannsperger, Heiko A.; McDermott, Elizabeth M.; Drewe, Elizabeth; Powell, Richard J.; Todd, Ian; Fairclough, Lucy C.; Tighe, Patrick J.

Authors

Ola H. Negm

Heiko A. Mannsperger

Elizabeth M. McDermott

Elizabeth Drewe

Richard J. Powell

Ian Todd

Lucy C. Fairclough

Patrick J. Tighe



Abstract

Mutations in TNFRSF1A encoding TNF receptor 1 (TNFR1) cause the autosomal dominant TNF receptor-associated periodic syndrome (TRAPS): a systemic autoinflammatory disorder. Misfolding, intracellular aggregation, and ligand-independent signaling by mutant TNFR1 are central to disease pathophysiology. Our aim was to understand the extent of signaling pathway perturbation in TRAPS. A prototypic mutant TNFR1 (C33Y), and wild-type TNFR1 (WT), were expressed at near physiological levels in an SK-Hep-1 cell model. TNFR1-associated signaling pathway intermediates were examined in this model, and in PBMCs from C33Y TRAPS patients and healthy controls. In C33Y-TNFR1-expressing SK-Hep-1 cells and TRAPS patients' PBMCs, a subtle, constitutive upregulation of a wide spectrum of signaling intermediates and their phosphorylated forms was observed; these were associated with a proinflammatory/antiapoptotic phenotype. In TRAPS patients' PBMCs, this upregulation of proinflammatory signaling pathways was observed irrespective of concurrent treatment with glucocorticoids, anakinra or etanercept, and the absence of overt clinical symptoms at the time that the blood samples were taken. This study reveals the pleiotropic effect of a TRAPS-associated mutant form of TNFR1 on inflammatory signaling pathways (a proinflammatory signalome), which is consistent with the variable and limited efficacy of cytokine-blocking therapies in TRAPS. It highlights new potential target pathways for therapeutic intervention.

Journal Article Type Article
Publication Date Jul 1, 2014
Journal European Journal of Immunology
Print ISSN 0014-2980
Electronic ISSN 1521-4141
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 44
Issue 7
APA6 Citation Negm, O. H., Mannsperger, H. A., McDermott, E. M., Drewe, E., Powell, R. J., Todd, I., …Tighe, P. J. (2014). A pro-inflammatory signalome is constitutively activated by C33Y mutant TNF receptor 1 in TNF receptor-associated periodic syndrome (TRAPS). European Journal of Immunology, 44(7), doi:10.1002/eji.201344328
DOI https://doi.org/10.1002/eji.201344328
Keywords Autoinflammation; Protein microarray; Signalome; TNF receptor 1; TRAPS
Publisher URL http://onlinelibrary.wiley.com/doi/10.1002/eji.201344328/abstract
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by-nc-nd/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by-nc-nd/4.0





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