Journal
CELL CYCLE
Volume 13, Issue 8, Pages 1306-1312Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.28256
Keywords
Jak3; IL-17F; CTCL; IL-15; STAT3; MF
Categories
Funding
- Carlsberg Foundation
- Danish Cancer Society
- Dansk Kraeftforsknings Fond
- Danish Research Councils
- Danish National Advanced Technology Foundation
- Copenhagen Cluster of Immunology
- Lundbeck Foundation
- Novo Nordic Foundation
- Neye Foundation
- Beckett Foundation (Beckett-Fonden)
- University of Copenhagen
- National Cancer Institute [CA89194]
- Canadian Dermatology Foundation
- Le Fonds de Recherche du Quebec-Sante
- Novo Nordisk Fonden [NNF12OC0002036] Funding Source: researchfish
- The Danish Cancer Society [R72-A4571] Funding Source: researchfish
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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, Sezary 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.
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