Malignant Cutaneous T-Cell Lymphoma Cells Express IL-17 Utilizing the Jak3/Stat3 Signaling Pathway

Abstract

IL-17 is a proinflammatory cytokine that is crucial for the host's protection against a range of extracellular pathogens. However, inappropriately regulated expression of IL-17 is associated with the development of inflammatory diseases and cancer. In cutaneous T-cell lymphoma (CTCL), malignant T cells gradually accumulate in skin lesions characterized by massive chronic inflammation, suggesting that IL-17 could be involved in the pathogenesis. In this study we show that IL-17 protein is present in 10 of 13 examined skin lesions but not in sera from 28 CTCL patients. Importantly, IL-17 expression is primarily observed in atypical lymphocytes with characteristic neoplastic cell morphology. In accordance, malignant T-cell lines from CTCL patients produce IL-17 and the synthesis is selectively increased by IL-2 receptor β chain cytokines. Small-molecule inhibitors or small interfering RNA against Jak3 and signal transducer and activator of transcription 3 (Stat3) reduce the production of IL-17, showing that the Jak3/Stat3 pathway promotes the expression of the cytokine. In summary, our findings indicate that the malignant T cells in CTCL lesions express IL-17 and that this expression is promoted by the Jak3/Stat3 pathway.

Analysis of STAT4 expression in cutaneous T-cell lymphoma (CTCL) patients and patient-derived cell lines

“…IL-9 (Th9 marker) was only detected in MyLa cells upon stimulation with CD3/CD28 Dynabeads Ò , while most CTCL cell lines were IL-9-negative. Consistent with previous reports, 32,36,37 MyLa, PB2B, SZ4, Sez4 Hut102 and SeAx cells express IL-17F, IL-17A or both. Furthermore, these cytokines were further upregulated upon T cell stimulation ( Fig.…”

STAT5-mediated expression of oncogenic miR-155 in cutaneous T-cell lymphoma

“…41 All cell lines were cultured as described previously. 26,29,30,[49][50][51] Peripheral blood mononuclear cells (PBMCs) from a healthy donor were isolated by density gradient centrifugation using Lymphoprep (Axis-Shield, PoC AS) as CTCL patients as well as PBMCs from healthy individuals also display a significant upregulation of BIC/miR-155 upon STAT5 activation by IL-2Rβγ cytokines (IL-2 and IL-15), indicating that transcriptional regulation of BIC by STAT5 is not a unique feature of malignant T cells, but a common regulatory pathway.…”

“…Malignant T cells lines (MyLa2059, PB2B, SeAx and SeZ4.1) and non-malignant T cell lines (MySi, MyLa1850) were obtained from CTCL patients and have been described perviously. 26,29,30,49 MAC2A is an anaplastic large T-cell lymphoma (ALCL) cell line established from a skin tumor in the progressive phase of the disease. 50 The Jurkat cell line (J-Tag) has been described elsewhere.…”

“…described before. 52 PBMCs from three patients diagnosed with SS were isolated as described before 29 and sorted to yield CD4+/ CD26 − as well as CD4+/CD26+ populations. After sorting, both populations were cultured with and without IL-2 (2 × 10 3 U/ml, Proleukin, Chiron) for 24 h.…”

Overexpression of hypoxia‐inducible factor 1 alpha impacts FoxP3 levels in mycosis fungoides—Cutaneous T‐cell lymphoma: Clinical implications

“…1 T-cell differentiation that is predominant in the skin lesions of MF patients, [13][14][15][16][17] it has been consistently reported that the percentage of forkhead box P3 positive (FoxP3 1 ) cells decreases with disease progression.…”