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

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

doi:10.1182/blood-2015-08-662353

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

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^*

^*Corresponding author af dette arbejde

Institut for Klinisk Medicin

57 Citationer (Scopus)

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 b 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 g 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.

Originalsprog	Engelsk
Tidsskrift	Blood
Vol/bind	127
Udgave nummer	10
Sider (fra-til)	1287-1296
Antal sider	10
ISSN	0006-4971
DOI	https://doi.org/10.1182/blood-2015-08-662353
Status	Udgivet - 10 mar. 2016

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10.1182/blood-2015-08-662353

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Willerslev-Olsen, A., Krejsgaard, T., Lindahl, L. M., Litvinov, I. V., Fredholm, S., Petersen, D. L., Nastasi, C., Gniadecki, R., Mongan, N. P., Sasseville, D., Wasik, M. A., Bonefeld, C. M., Geisler, C., Woetmann, A., Iversen, L., Kilian, M., Koralov, S. B., & Odum, N. (2016). Staphylococcal 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

Willerslev-Olsen, A, Krejsgaard, T, Lindahl, LM, Litvinov, IV, Fredholm, S, Petersen, DL, Nastasi, C, Gniadecki, R, Mongan, NP, Sasseville, D, Wasik, MA, Bonefeld, CM, Geisler, C , Woetmann, A, Iversen, L, Kilian, M, Koralov, SB & Odum, N 2016, 'Staphylococcal enterotoxin A (SEA) stimulates STAT3 activation and IL-17 expression in cutaneous T-cell lymphoma', Blood, bind 127, nr. 10, s. 1287-1296. https://doi.org/10.1182/blood-2015-08-662353

@article{f25205e7a0a04133a4b2beb00d5f8732,

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

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 b 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 g 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.",

author = "Andreas Willerslev-Olsen and Thorbj{\o}rn Krejsgaard and Lindahl, {Lise M.} and Litvinov, {Ivan V.} and Simon Fredholm and Petersen, {David L.} and Claudia Nastasi and Robert Gniadecki and Mongan, {Nigel P.} and Denis Sasseville and Wasik, {Mariusz A.} and Bonefeld, {Charlotte M.} and Carsten Geisler and Anders Woetmann and Lars Iversen and Mogens Kilian and Koralov, {Sergei B.} and Niels Odum",

year = "2016",

month = mar,

day = "10",

doi = "10.1182/blood-2015-08-662353",

language = "English",

volume = "127",

pages = "1287--1296",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

number = "10",

}

TY - JOUR

T1 - Staphylococcal enterotoxin A (SEA) stimulates STAT3 activation and IL-17 expression in cutaneous T-cell lymphoma

AU - Willerslev-Olsen, Andreas

AU - Krejsgaard, Thorbjørn

AU - Lindahl, Lise M.

AU - Litvinov, Ivan V.

AU - Fredholm, Simon

AU - Petersen, David L.

AU - Nastasi, Claudia

AU - Gniadecki, Robert

AU - Mongan, Nigel P.

AU - Sasseville, Denis

AU - Wasik, Mariusz A.

AU - Bonefeld, Charlotte M.

AU - Geisler, Carsten

AU - Woetmann, Anders

AU - Iversen, Lars

AU - Kilian, Mogens

AU - Koralov, Sergei B.

AU - Odum, Niels

PY - 2016/3/10

Y1 - 2016/3/10

N2 - 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 b 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 g 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.

AB - 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 b 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 g 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.

U2 - 10.1182/blood-2015-08-662353

DO - 10.1182/blood-2015-08-662353

M3 - Journal article

C2 - 26738536

AN - SCOPUS:84960872280

SN - 0006-4971

VL - 127

SP - 1287

EP - 1296

JO - Blood

JF - Blood

IS - 10

ER -

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

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