Staphylococcus aureus enterotoxin A (SEA) stimulates STAT3 activation and IL-17 expression in cutaneous T-cell lymphoma
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 malign...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
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American Society of Hematology
2016
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| Online Access: | https://eprints.nottingham.ac.uk/31255/ |
| _version_ | 1848794161097998336 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Willerslev-Olsen, Andreas |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T19:11:47Z |
| format | Article |
| id | nottingham-31255 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:11:47Z |
| publishDate | 2016 |
| publisher | American Society of Hematology |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-312552020-05-04T17:42:19Z https://eprints.nottingham.ac.uk/31255/ 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 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. American Society of Hematology 2016-03-10 Article PeerReviewed 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 and Odum, Niels (2016) Staphylococcus aureus enterotoxin A (SEA) stimulates STAT3 activation and IL-17 expression in cutaneous T-cell lymphoma. Blood, 127 (10). pp. 1287-1296. ISSN 1528-0020 http://www.bloodjournal.org/content/early/2016/01/05/blood-2015-08-662353 doi:10.1182/blood-2015-08-662353 doi:10.1182/blood-2015-08-662353 |
| spellingShingle | 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 Staphylococcus aureus enterotoxin A (SEA) stimulates STAT3 activation and IL-17 expression in cutaneous T-cell lymphoma |
| title | Staphylococcus aureus enterotoxin A (SEA) stimulates STAT3 activation and IL-17 expression in cutaneous T-cell lymphoma |
| title_full | Staphylococcus aureus enterotoxin A (SEA) stimulates STAT3 activation and IL-17 expression in cutaneous T-cell lymphoma |
| title_fullStr | Staphylococcus aureus enterotoxin A (SEA) stimulates STAT3 activation and IL-17 expression in cutaneous T-cell lymphoma |
| title_full_unstemmed | Staphylococcus aureus enterotoxin A (SEA) stimulates STAT3 activation and IL-17 expression in cutaneous T-cell lymphoma |
| title_short | Staphylococcus aureus enterotoxin A (SEA) stimulates STAT3 activation and IL-17 expression in cutaneous T-cell lymphoma |
| title_sort | staphylococcus aureus enterotoxin a (sea) stimulates stat3 activation and il-17 expression in cutaneous t-cell lymphoma |
| url | https://eprints.nottingham.ac.uk/31255/ https://eprints.nottingham.ac.uk/31255/ https://eprints.nottingham.ac.uk/31255/ |