Willerslev-Olsen, Andreas8; Litvinov, Ivan V4; Fredholm, Simon M8; Petersen, David L8; Sibbesen, Nina A8; Gniadecki, Robert5; Zhang, Qian6; Bonefeld, Charlotte M8; Wasik, Mariusz A6; Geisler, Carsten9; Zhou, Youwen7; Woetmann, Anders8; Sasseville, Denis4; Krejsgaard, Thorbjørn8; Ødum, Niels8
1 Department of Immunology and Microbiology, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, Københavns Universitet2 Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, Københavns Universitet3 Cell Biology and Physiology, Department of Biology, Faculty of Science, Københavns Universitet4 Division of Dermatology; McGill University Health Centre; Montréal, Quebec, Canada.5 Departmen of Dermatology; Copenhagen University Hospital; Bispebjerg, Copenhagen, Denmark.6 Department of Pathology and Laboratory Medicine; University of Pennsylvania; Philadelphia, PA USA.7 Department of Dermatology and Skin Science; University of British Columbia; Vancouver, British Columbia, Canada.8 Department of Immunology and Microbiology, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, Københavns Universitet9 Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, Københavns Universitet
Skin lesions from mycosis fungoides (MF) patients display an increased expression of interleukin-15 (IL-15), IL-17F, and other cytokines implicated in inflammation and malignant cell proliferation in cutaneous T-cell lymphoma (CTCL). In the leukemic variant of CTCL, Sézary syndrome (SS), IL-2 and IL-15 trigger activation of the Jak-3/STAT3 pathway and transcription of IL17A gene, whereas it is unknown what causes IL-15 expression, Jak3/STAT3 activation, and production of IL-17F in MF. Here, we studied the expression and regulation of IL-15 and its relation to IL-17F in MF cell lines and skin lesions from 60 MF patients. We show that: (1) the spontaneous IL-15 mRNA expression is resistant to Jak3 and STAT3 inhibitors at concentrations that profoundly inhibit STAT3 activation and IL-17F mRNA expression; (2) anti-IL-15 antibody blocks STAT3 activation induced by exogenous IL-15 in non-malignant MF T cells, whereas the spontaneous STAT3 activation and IL-17F expression in malignant T cells is not inhibited; (3) patients display heterogeneous IL-15/IL-17F mRNA expression patterns in skin lesions; and (4) IL-15 expression (in contrast to IL-17F) is not associated with progressive disease. Taken together, these findings indicate that IL-15 and IL-17F are differentially regulated and expressed in MF. We propose that IL-15 and IL-17F are markers for different inflammatory environments and play distinct roles in the development and progression of MF.