Volume 16 Supplement 1

Lupus 2014: New Targets, New Approaches

Open Access

Elucidating the role of TNF-like weak inducer of apoptosis in the pathogenesis of cutaneous lupus

  • Jessica Doerner1,
  • Jing Wen1,
  • Yumin Xia1,
  • Adam Friedman1,
  • Jennifer Michaelson2,
  • Linda Burkly2,
  • Lan Wu2 and
  • Chaim Putterman1Email author
Arthritis Research & Therapy201416(Suppl 1):A26

https://doi.org/10.1186/ar4642

Published: 18 September 2014

Background

Cutaneous manifestations are very common in systemic lupus erythematosus (SLE). TNF-like weak inducer of apoptosis (TWEAK) is a soluble cytokine member of the TNF superfamily that binds to a sole receptor, Fn14. TWEAK/Fn14 signaling is involved in cell survival, apoptosis, cytokine production, and angiogenesis, and as such has been found to be important in both tissue repair and inflammatory diseases. Whether TWEAK is involved in autoimmune skin disease is not known.

Methods

To evaluate a possible role for TWEAK in the pathogenesis of cutaneous lupus, we generated a lupus-prone mouse strain, MRL-lpr/lpr (MRL/lpr), deficient in Fn14, and evaluated the development of skin disease in this strain as compared with age and gender-matched MRL/lpr mice. In vitro studies using a keratinocyte cell line, PAM212, were performed to evaluate the effects of TWEAK and ultraviolet B (UVB) irradiation on apoptosis and cytokine production.

Results

We found that lupus-prone MRL/lpr mice deficient for Fn14 (Fn14KO) had markedly attenuated cutaneous disease as compared with Fn14WT mice. MRL/lpr Fn14KO mice had significantly less epidermal acanthosis and follicular plugging, and there was decreased infiltration of T cells and macrophages as compared with Fn14WT mice. In vitro, TWEAK treatment of murine keratinocytes stimulated the secretion of RANTES (via Fn14), and promoted apoptosis. Parthenolide decreased production of RANTES, indicating that this effect of TWEAK is mediated via NF-κB. Ultraviolet light, specifically UVB, is recognized as a potent trigger of cutaneous lupus. We found that TWEAK co-treatment exacerbates UVB light-induced keratinocyte apoptosis and increases the amount of RANTES secreted, when compared with cells treated with UVB alone. These synergistic effects of TWEAK+UVB on keratinocytes were probably due to upregulation of Fn14 expression by UVB.

Conclusions

Our data strongly implicate TWEAK/Fn14 signaling in the pathogenesis of the cutaneous manifestations of lupus.

Declarations

Acknowledgements

The authors would like to thank Dr Nancy Bigley (Wright State University, Dayton, OH, USA) for the kind gift of PAM212 keratinocytes.

Authors’ Affiliations

(1)
Albert Einstein College of Medicine
(2)
Biogen Idec, Inc.

Copyright

© Doerner et al.; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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