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

Willerslev-Olsen, Andreas and Krejsgaard, Thorbjørn and Lindahl, Lise M. and Litvinov, Ivan V. and Fredholm, Simon and Petersen, David L. and Nastasi, Claudia and Gniadecki, Robert and Mongan, Nigel P. and Sasseville, Denis and Wasik, Mariusz A. and Bonefeld, Charlotte M. and Geisler, Carsten and Woetmann, Anders and Iversen, Lars and Kilian, Mogens and Koralov, Sergei B. and Odum, Niels (2016) Staphylococcal enterotoxin A (SEA) stimulates STAT3 activation and IL-17 expression in cutaneous T-cell lymphoma. Blood, 127 (10). pp. 1287-1296. ISSN 1528-0020

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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 of 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 signal transducer and activator of transcription 3 (STAT3) and upregulation of interleukin (IL)-17 in immortalized and primary patient-derived malignant and nonmalignant T cells. Importantly, SEA induces STAT3 activation and IL-17 expression in malignant T cells when cocultured with nonmalignant T cells, indicating an indirect mode of action. In accordance, malignant T cells expressing an SEA-nonresponsive T-cell receptor variable region β chain are nonresponsive to SEA in monoculture but display strong STAT3 activation and IL-17 expression in cocultures with SEA-responsive nonmalignant T cells. The response is induced via IL-2 receptor common γ chain 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 whereby SEA-producing bacteria promote activation of an established oncogenic pathway previously implicated in carcinogenesis.

Item Type: Article
Additional Information: This research was originally published in Blood Online. Andreas Willerslev-Olsen, Thorbjørn Krejsgaard, Lise M. Lindahl, Ivan V. Litvinov, Simon Fredholm, David L. Petersen, Claudia Nastasi, Robert Gniadecki, Nigel P. Mongan, Denis Sasseville, Mariusz A. Wasik, Charlotte M. Bonefeld, Carsten Geisler, Anders Woetmann, Lars Iversen, Mogens Kilian, Sergei B. Koralov, Niels Odum. Staphylococcal enterotoxin A (SEA) stimulates STAT3 activation and IL-17 expression in cutaneous T-cell lymphoma. Blood. Prepublished January 5, 2016; DOI 10.1182/blood-2015-08-662353
Schools/Departments: University of Nottingham UK Campus > Faculty of Medicine and Health Sciences > School of Veterinary Medicine and Science
Identification Number: https://doi.org/10.1182/blood-2015-08-662353
Depositing User: Mongan, Nigel
Date Deposited: 15 Sep 2016 13:41
Last Modified: 15 Sep 2016 13:50
URI: http://eprints.nottingham.ac.uk/id/eprint/36666

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