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 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.
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Andreas
authors.initials: A
authors.lastname: Willerslev-Olsen
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Thorbjørn
authors.initials: T
authors.lastname: Krejsgaard
authors.affiliation: Department of Dermatology, Aarhus University Hospital, Skejby, Aarhus, Denmark;
authors.forename: Lise M
authors.initials: LM
authors.lastname: Lindahl
authors.affiliation: Division of Dermatology, University of Ottawa, Ottawa, ON, Canada;
authors.forename: Ivan V
authors.initials: IV
authors.lastname: Litvinov
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Simon
authors.initials: S
authors.lastname: Fredholm
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark;
authors.forename: David L
authors.initials: DL
authors.lastname: Petersen
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Claudia
authors.initials: C
authors.lastname: Nastasi
authors.affiliation: Department of Dermatology, Copenhagen University Hospital, Bispebjerg, Copenhagen, Denmark;
authors.forename: Robert
authors.initials: R
authors.lastname: Gniadecki
authors.affiliation: Faculty of Medicine and Health Science, School of Veterinary Medicine and Science, University of Nottingham, Loughborough, United Kingdom;
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Mongan
authors.affiliation: Division of Dermatology, McGill University Health Centre, Montréal, QC, Canada;
authors.forename: Denis
authors.initials: D
authors.lastname: Sasseville
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA;
authors.forename: Mariusz A
authors.initials: MA
authors.lastname: Wasik
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Bonefeld
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Carsten
authors.initials: C
authors.lastname: Geisler
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Anders
authors.initials: A
authors.lastname: Woetmann
authors.affiliation: Department of Dermatology, Aarhus University Hospital, Skejby, Aarhus, Denmark;
authors.forename: Lars
authors.initials: L
authors.lastname: Iversen
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark; and.
authors.forename: Mogens
authors.initials: M
authors.lastname: Kilian
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY.
authors.forename: Sergei B
authors.initials: SB
authors.lastname: Koralov
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Niels
authors.initials: N
authors.lastname: Odum
mesh_terms: D045744:Cell Line, Tumor; D018920:Coculture Techniques; D004768:Enterotoxins / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000378:metabolism; D020381:Interleukin-17 / Q000096:biosynthesis*; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D009363:Neoplasm Proteins / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D012751:Sezary Syndrome / Q000378:metabolism* / Q000473:pathology; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology
chemical_list: D004768:Enterotoxins; C507941:IL2RG protein, human; D053631:Interleukin Receptor Common gamma Subunit; D020381:Interleukin-17; D009363:Neoplasm Proteins; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C026066:enterotoxin A, Staphylococcal; C479163:tofacitinib