title: Autocrine IL-21 stimulation is involved in the maintenance of constitutive STAT3 activation in Sézary syndrome.
abstract: Sézary syndrome (SS) is a cutaneous T-cell lymphoma (CTCL) with malignant CD4+ T cells (SS cells) in skin, lymph nodes, and blood. Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in SS cells, whereas this activation is lost upon in vitro culturing, indicating that STAT3 activation observed in vivo is the result of activating factors in the micromilieu of the malignant cells. We investigated which factors are involved in STAT3 activation in SS, focusing on cytokines of the common γ-chain family because of their crucial role in T-cell activation. Furthermore, downstream effects of STAT3 signaling in SS cells were assayed. In SS cells, STAT3 was strongly activated by IL-21, and increased expression of IL-21 and its receptor chains was observed in peripheral blood SS cells. IL-21 and IL-21R protein expression was detectable on neoplastic cells in SS skin biopsies. Using short-term culturing experiments, we demonstrate that IL-21 itself and the α-chain of the IL-2 receptor are STAT3 target genes in SS cells, thereby rendering cells more sensitive to stimulation with the T-cell proliferation and activating cytokine IL-2. Combined, our data point toward a pivotal role for an autocrine positive feedback loop involving IL-21 and consequent persistent STAT3 activation in the pathogenesis of SS, thereby indicating IL-21 and IL-21R as new therapeutical targets.
authors.affiliation: Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands. L.vanderfits@lumc.nl
authors.forename: Leslie
authors.initials: L
authors.lastname: van der Fits
authors.forename: Jacoba J
authors.initials: JJ
authors.lastname: Out-Luiting
authors.forename: Marieke A
authors.initials: MA
authors.lastname: van Leeuwen
authors.forename: Janneke N
authors.initials: JN
authors.lastname: Samsom
authors.forename: Rein
authors.initials: R
authors.lastname: Willemze
authors.forename: Cornelis P
authors.initials: CP
authors.lastname: Tensen
authors.forename: Maarten H
authors.initials: MH
authors.lastname: Vermeer
mesh_terms: D019898:Autocrine Communication; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D007378:Interleukins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D053655:Receptors, Interleukin-21 / Q000032:analysis; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D012751:Sezary Syndrome / Q000209:etiology / Q000276:immunology*; D012878:Skin Neoplasms / Q000276:immunology*; D000098546:Interleukin-21
chemical_list: D007376:Interleukin-2; D007378:Interleukins; D053655:Receptors, Interleukin-21; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000098546:Interleukin-21