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Staphylococcus aureus enterotoxin A (SEA) stimulates STAT3 activation and IL-17 expression in cutaneous T-cell lymphoma

Willerslev-Olsen, Andreas; Krejsgaard, Thorbjørn; Lindahl, Lise M.; Litvinov, Ivan V.; Fredholm, Simon; Petersen, David L.; Nastasi, Claudia; Gniadecki, Robert; Mongan, Nigel P.; Sasseville, Denis; Wasik, Mariusz A.; Bonefeld, Charlotte M.; Geisler, Carsten; Woetmann, Anders; Iversen, Lars; Kilian, Mogens; Koralov, Sergei; Odum, Niels

Authors

Andreas Willerslev-Olsen

Thorbjørn Krejsgaard

Lise M. Lindahl

Ivan V. Litvinov

Simon Fredholm

David L. Petersen

Claudia Nastasi

Robert Gniadecki

Denis Sasseville

Mariusz A. Wasik

Charlotte M. Bonefeld

Carsten Geisler

Anders Woetmann

Lars Iversen

Mogens Kilian

Sergei Koralov

Niels Odum



Abstract

Cutaneous T cell lymphoma (CTCL) is characterized by proliferation of malignant T cells in a chronic inflammatory environment. With disease progression, bacteria colonize the compromised skin barrier and half of CTCL patients die from infection rather than from direct organ involvement by the malignancy. Clinical data indicate that bacteria play a direct role in disease progression, but little is known about the mechanisms involved. Here, we demonstrate that bacterial isolates containing staphylococcal enterotoxin-A (SEA) from the affected skin of CTCL patients, as well as recombinant SEA, stimulate activation of STAT3 and up-regulation of IL-17 in immortalized and primary patient-derived malignant and non-malignant T cells. Importantly, SEA induces STAT3 activation and IL-17 expression in malignant T cells when co-cultured with non-malignant T cells indicating an indirect mode of action. In accordance, malignant T cells expressing a SEA non-responsive T cell receptor V beta chain (TCR-Vb) are non-responsive to SEA in mono-culture, but display strong STAT3 activation and IL-17 expression in co-cultures with SEA-responsive, non-malignant T cells. The response is induced via IL-2Rg cytokines and a Janus kinase 3 (JAK3) - dependent pathway in malignant T cells and blocked by Tofacitinib, a clinical-grade JAK3 inhibitor. In conclusion, we demonstrate that SEA induces cell cross-talk-dependent activation of STAT3 and expression of IL-17 in malignant T cells suggesting a mechanism where SEA-producing bacteria promote activation of an established oncogenic pathway previously implicated in carcinogenesis.

Citation

Willerslev-Olsen, A., Krejsgaard, T., Lindahl, L. M., Litvinov, I. V., Fredholm, S., Petersen, D. L., …Odum, N. (2016). Staphylococcus aureus enterotoxin A (SEA) stimulates STAT3 activation and IL-17 expression in cutaneous T-cell lymphoma. Blood, 127(10), 1287-1296. https://doi.org/10.1182/blood-2015-08-662353

Journal Article Type Article
Acceptance Date Dec 1, 2015
Online Publication Date Jan 5, 2016
Publication Date Mar 10, 2016
Deposit Date Jan 28, 2016
Publicly Available Date Jan 6, 2017
Journal Blood
Print ISSN 0006-4971
Electronic ISSN 1528-0020
Publisher American Society of Hematology
Peer Reviewed Peer Reviewed
Volume 127
Issue 10
Pages 1287-1296
DOI https://doi.org/10.1182/blood-2015-08-662353
Public URL http://eprints.nottingham.ac.uk/id/eprint/31255
Publisher URL http://www.bloodjournal.org/content/127/10/1287
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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