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1.
Oncoimmunology ; 11(1): 2115655, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36052217

RESUMO

CCL22 is a macrophage-derived immunosuppressive chemokine that recruits regulatory T cells through the CCL22:CCR4 axis. CCL22 was shown to play a key role in suppressing anti-cancer immune responses in different cancer types. Recently, we showed that CCL22-specific T cells generated from cancer patients could kill CCL22-expressing tumor cells and directly influence the levels of CCL22 in vitro. The present study aimed to provide a rationale for developing a CCL22-targeting immunotherapy. Vaccination with CCL22-derived peptides induced CCL22-specific T-cell responses in both BALB/c and C57BL/6 mice, assessed by interferon-γ secretion ex vivo. Anti-tumor efficacy of the peptides was evaluated in mouse models engrafted with syngeneic tumor models showing a reduced tumor growth and prolonged survival of the treated mice. Vaccination induced changes in the cellular composition of immune cells that infiltrated the tumor microenvironment assessed with multicolor flow cytometry. In particular, the infiltration of CD8+ cells and M1 macrophages increased, which increased the CD8/Treg and the M1/M2 macrophage ratio. This study provided preclinical evidence that targeting CCL22 with CCL22 peptide vaccines modulated the immune milieu in the tumor microenvironment. This modulation led to an augmentation of anti-tumor responses. This study provided a rationale for developing a novel immunotherapeutic modality in cancer.


Assuntos
Neoplasias , Microambiente Tumoral , Animais , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias/patologia , Linfócitos T Reguladores , Vacinas de Subunidades Antigênicas
2.
J Immunother Cancer ; 8(2)2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32690770

RESUMO

BACKGROUND: The tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1), which subverts T-cell immunity at multiple levels, is itself subject to inherent T-cell reactivity. This intriguing deviation from central tolerance has been interpreted as counterbalancing IDO1-mediated immunosuppression. Based on this hypothesis, clinical studies employing an IDO1 peptide-based vaccine approach for cancer treatment have been initiated, but there remains a pressing need to further investigate the immunological ramifications of stimulating the anti-IDO1 T-cell response in this manner. METHODS: CT26 colon carcinoma tumors were evaluated for expression of IDO1 protein by western blot analysis, immunofluorescence microscopy and flow cytometry. Mouse IDO1-derived peptides, predicted to bind either major histocompatibility complex (MHC) class I or II of the H2d BALB/c strain, were emulsified in 50% Montanide for prophylactic or therapeutic vaccine treatment of CT26 tumor-bearing mice initiated either 7 days prior to or following tumor cell injection, respectively. In some therapeutic treatment experiments, administration of programmed cell death protein 1-binding antibody (anti-PD1 antibody) or epacadostat was concurrently initiated. Tumor size was determined by caliper measurements and comparative tumor growth suppression was assessed by longitudinal analyses of tumor growth data. For adoptive transfer, T cells from complete responder animals were isolated using paramagnetic beads and fluorescence-activated cell sorting. RESULTS: This study identifies mouse MHC class I-directed and II-directed, IDO1-derived peptides capable of eliciting antitumor responses, despite finding IDO1 expressed exclusively in tumor-infiltrating immune cells. Treatment of established tumors with anti-PD1 antibody and class I-directed but not class II-directed IDO1 peptide vaccines produced an enhanced antitumor response. Likewise, class I-directed and II-directed IDO1 peptides elicited an enhanced combinatorial response, suggesting distinct mechanisms of action. Consistent with this interpretation, adoptive transfer of isolated CD8+ T cells from class I and CD4+ T cells from class II peptide-vaccinated responder mice delayed tumor growth. The class II-directed response was completely IDO1-dependent while the class I-directed response included an IDO1-independent component consistent with antigen spread. CONCLUSIONS: The in vivo antitumor effects demonstrated with IDO1-based vaccines via targeting of the tumor microenvironment highlight the utility of mouse models for further exploration and refinement of this novel vaccine-based approach to IDO1-directed cancer therapy and its potential to improve patient response rates to anti-PD1 therapy.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/uso terapêutico , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Vacinas de Subunidades Antigênicas/uso terapêutico , Animais , Vacinas Anticâncer/farmacologia , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Transgênicos , Vacinas de Subunidades Antigênicas/farmacologia
3.
Chin Clin Oncol ; 7(2): 19, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29764164

RESUMO

Historically, the development of cancer vaccines has focused on the central role of tumor antigens in eliciting tumor-specific immune responses, with limited success. Recent advances with checkpoint blockade approaches have brought about a renewed appreciation of the importance of targeting immune suppression in cancer patients. Here we discuss a novel approach to cancer immunotherapy, namely to target recently described T cells that uniquely control cells with immune suppressive functions. Accumulating evidence support the existence of self-reactive T cells that are specific to antigens derived from immunoregulatory proteins ("immunoregulatory antigens"), such as indoleamine 2,3-dioxygenase (IDO) and PD-L1. Vaccination approaches to potentiate these T cells have proven safe with minimal toxicity in the clinical phase I trials conducted thus far. Given that immunoregulatory antigens can be new targets for cancer immunotherapy, we propose here that they could be considered as a new class of tumor antigens. Targeting such antigens has advantages over targeting classical tumor antigens, as there is no requirement for identification of relevant antigens that are specific for the cancer type, and the targets are genetically stable. Furthermore, targeting immunoregulatory antigen-specific T cells potentially has dual mode of actions (I) targeting immune suppression and thereby potentiating anti-tumor effector T cell responses and (II) direct killing of immunoregulatory antigen-expressing tumor cells.


Assuntos
Antígenos de Neoplasias/imunologia , Imunoterapia/métodos , Humanos
4.
J Invest Dermatol ; 138(8): 1805-1815, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29751003

RESUMO

Deficient expression of SATB1 hampers thymocyte development and results in inept T-cell lineages. Recent data implicate dysregulated SATB1 expression in the pathogenesis of mycosis fungoides, the most frequent variant of cutaneous T-cell lymphoma. Here, we report on a disease stage-associated decrease of SATB1 expression and an inverse expression of STAT5 and SATB1 in situ. STAT5 inhibited SATB1 expression through induction of microRNA-155. Decreased SATB1 expression triggered enhanced expression of IL-5 and IL-9 (but not IL-6 and IL-32), whereas increased SATB1 expression had the opposite effect, indicating that the microRNA-155 target SATB1 is a repressor of IL-5 and IL-9 in malignant T cells. In accordance, inhibition of STAT5 and its upstream activator JAK3 triggered increased SATB1 expression and a concomitant suppression of IL-5 and IL-9 expression in malignant T cells. In conclusion, we provide a mechanistic link between the proto-oncogenic JAK3/STAT5/microRNA-155 pathway, SATB1, and cytokines linked to CTCL severity and progression, indicating that SATB1 dysregulation is involved in cutaneous T-cell lymphoma pathogenesis.


Assuntos
Proteínas de Ligação à Região de Interação com a Matriz/genética , MicroRNAs/metabolismo , Micose Fungoide/genética , Neoplasias Cutâneas/genética , Linfócitos T/imunologia , Linhagem Celular Tumoral , Estudos de Coortes , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/imunologia , Técnicas de Silenciamento de Genes , Humanos , Interleucina-5/imunologia , Interleucina-5/metabolismo , Interleucina-9/imunologia , Interleucina-9/metabolismo , Janus Quinase 3/metabolismo , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , MicroRNAs/genética , MicroRNAs/imunologia , Micose Fungoide/imunologia , Micose Fungoide/patologia , Estadiamento de Neoplasias , RNA Interferente Pequeno/metabolismo , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Linfócitos T/metabolismo
5.
Oncotarget ; 6(24): 20555-69, 2015 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-26244872

RESUMO

Aberrant activation of Janus kinase-3 (Jak3) and its key down-stream effectors, Signal Transducer and Activator of Transcription-3 (STAT3) and STAT5, is a key feature of malignant transformation in cutaneous T-cell lymphoma (CTCL). However, it remains only partially understood how Jak3/STAT activation promotes lymphomagenesis. Recently, non-coding microRNAs (miRNAs) have been implicated in the pathogenesis of this malignancy. Here, we show that (i) malignant T cells display a decreased expression of a tumor suppressor miRNA, miR-22, when compared to non-malignant T cells, (ii) STAT5 binds the promoter of the miR-22 host gene, and (iii) inhibition of Jak3, STAT3, and STAT5 triggers increased expression of pri-miR-22 and miR-22. Curcumin, a nutrient with anti-Jak3 activity and histone deacetylase inhibitors (HDACi) also trigger increased expression of pri-miR-22 and miR-22. Transfection of malignant T cells with recombinant miR-22 inhibits the expression of validated miR-22 targets including NCoA1, a transcriptional co-activator in others cancers, as well as HDAC6, MAX, MYCBP, PTEN, and CDK2, which have all been implicated in CTCL pathogenesis. In conclusion, we provide the first evidence that de-regulated Jak3/STAT3/STAT5 signalling in CTCL cells represses the expression of the gene encoding miR-22, a novel tumor suppressor miRNA.


Assuntos
Janus Quinase 3/metabolismo , Linfoma Cutâneo de Células T/genética , MicroRNAs/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT5/metabolismo , Neoplasias Cutâneas/genética , Linhagem Celular Tumoral , Genes Supressores de Tumor , Humanos , Janus Quinase 3/antagonistas & inibidores , Janus Quinase 3/genética , Linfoma Cutâneo de Células T/metabolismo , Linfoma Cutâneo de Células T/patologia , MicroRNAs/administração & dosagem , MicroRNAs/biossíntese , MicroRNAs/genética , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT5/genética , Transdução de Sinais , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Transfecção
6.
Oncotarget ; 6(17): 15235-49, 2015 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-25915535

RESUMO

Lymphotoxin α (LTα) plays a key role in the formation of lymphatic vasculature and secondary lymphoid structures. Cutaneous T cell lymphoma (CTCL) is the most common primary lymphoma of the skin and in advanced stages, malignant T cells spreads through the lymphatic to regional lymph nodes to internal organs and blood. Yet, little is known about the mechanism of the CTCL dissemination. Here, we show that CTCL cells express LTα in situ and that LTα expression is driven by aberrantly activated JAK3/STAT5 pathway. Importantly, via TNF receptor 2, LTα functions as an autocrine factor by stimulating expression of IL-6 in the malignant cells. LTα and IL-6, together with VEGF promote angiogenesis by inducing endothelial cell sprouting and tube formation. Thus, we propose that LTα plays a role in malignant angiogenesis and disease progression in CTCL and may serve as a therapeutic target in this disease.


Assuntos
Interleucina-6/metabolismo , Linfoma Cutâneo de Células T/patologia , Linfotoxina-alfa/metabolismo , Neoplasias Cutâneas/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Sítios de Ligação/genética , Proteínas de Ligação a DNA/metabolismo , Células Endoteliais/metabolismo , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Janus Quinase 3/genética , Janus Quinase 3/metabolismo , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Neovascularização Patológica/patologia , Regiões Promotoras Genéticas/genética , Interferência de RNA , RNA Interferente Pequeno , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismo , Linfócitos T/patologia , Células Tumorais Cultivadas , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
7.
Proc Natl Acad Sci U S A ; 111(39): E4066-75, 2014 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-25118277

RESUMO

Aberrant expression of immature truncated O-glycans is a characteristic feature observed on virtually all epithelial cancer cells, and a very high frequency is observed in early epithelial premalignant lesions that precede the development of adenocarcinomas. Expression of the truncated O-glycan structures Tn and sialyl-Tn is strongly associated with poor prognosis and overall low survival. The genetic and biosynthetic mechanisms leading to accumulation of truncated O-glycans are not fully understood and include mutation or dysregulation of glycosyltransferases involved in elongation of O-glycans, as well as relocation of glycosyltransferases controlling initiation of O-glycosylation from Golgi to endoplasmic reticulum. Truncated O-glycans have been proposed to play functional roles for cancer-cell invasiveness, but our understanding of the biological functions of aberrant glycosylation in cancer is still highly limited. Here, we used exome sequencing of most glycosyltransferases in a large series of primary and metastatic pancreatic cancers to rule out somatic mutations as a cause of expression of truncated O-glycans. Instead, we found hypermethylation of core 1 ß3-Gal-T-specific molecular chaperone, a key chaperone for O-glycan elongation, as the most prevalent cause. We next used gene editing to produce isogenic cell systems with and without homogenous truncated O-glycans that enabled, to our knowledge, the first polyomic and side-by-side evaluation of the cancer O-glycophenotype in an organotypic tissue model and in xenografts. The results strongly suggest that truncation of O-glycans directly induces oncogenic features of cell growth and invasion. The study provides support for targeting cancer-specific truncated O-glycans with immunotherapeutic measures.


Assuntos
Neoplasias Pancreáticas/metabolismo , Polissacarídeos/química , Polissacarídeos/metabolismo , Animais , Adesão Celular , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Exoma/genética , Glicômica , Glicosilação , Xenoenxertos , Humanos , Camundongos , Camundongos Knockout , Camundongos Nus , Camundongos SCID , Chaperonas Moleculares/química , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Mutação , Invasividade Neoplásica , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Fenótipo , Proteômica , Transdução de Sinais
9.
APMIS ; 121(11): 1020-4, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24033365

RESUMO

Recently, miR-155 has been implicated in cutaneous T-cell lymphoma (CTCL). Thus, elevated levels of miR-155 were observed in skin lesions from CTCL patients as judged from qPCR and micro-array analysis and aberrant, high miR-155 expression was associated with severe disease. Moreover, miR-155 promoted proliferation of malignant T cells in vitro. Little is, however, known about which cell types express miR-155 in vivo in CTCL skin lesions. Here, we study miR-155 expression using in situ hybridization (ISH) with a miR-155 probe, a negative control (scrambled), and a miR-126 probe as a positive control in nine patients with mycosis fungoides, the most frequent subtype of CTCL. We provide evidence that both malignant and non-malignant T cells stain weakly to moderately positive with the miR-155 probe, but generally negative with the miR-126 and negative control probes. Reversely, endothelial cells stain positive for miR-126 and negative for miR-155 and the control probe. Solitary T cells with a malignant morphology display brighter staining with the miR-155 probe. Taken together, our findings suggest that both malignant and non-malignant T cells express miR-155 in situ in CTCL. Moreover, they indicate heterogeneity in miR-155 expression among malignant T cells.


Assuntos
Linfoma Cutâneo de Células T/genética , MicroRNAs/fisiologia , Neoplasias Cutâneas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Hibridização In Situ , Masculino , MicroRNAs/análise , Pessoa de Meia-Idade
10.
Blood ; 122(6): 943-50, 2013 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-23801634

RESUMO

Inappropriately regulated expression of interleukin (IL)-17A is associated with the development of inflammatory diseases and cancer. However, little is known about the role of other IL-17 family members in carcinogenesis. Here, we show that a set of malignant T-cell lines established from patients with cutaneous T-cell lymphoma (CTCL) spontaneously secrete IL-17F and that inhibitors of Janus kinases and Signal transducer and activator of transcription 3 are able to block that secretion. Other malignant T-cell lines produce IL-17A but not IL-17F. Upon activation, however, some of the malignant T-cell lines are able to coexpress IL-17A and IL-17F, leading to formation of IL-17A/F heterodimers. Clinically, we demonstrate that IL-17F messenger RNA expression is significantly increased in CTCL skin lesions compared with healthy donors and patients with chronic dermatitis. IL-17A expression is also increased and a significant number of patients express high levels of both IL-17A and IL-17F. Concomitantly, we observed that the expression of the IL-17 receptor is significantly increased in CTCL skin lesions compared with control subjects. Importantly, analysis of a historic cohort of 60 CTCL patients indicates that IL-17F expression is associated with progressive disease. These findings implicate IL-17F in the pathogenesis of CTCL and suggest that IL-17 cytokines and their receptors may serve as therapeutic targets.


Assuntos
Regulação Neoplásica da Expressão Gênica , Regulação da Expressão Gênica , Interleucina-17/metabolismo , Linfoma Cutâneo de Células T/metabolismo , Biópsia , Linhagem Celular Tumoral , Citocinas/metabolismo , Progressão da Doença , Feminino , Humanos , Janus Quinases/metabolismo , Células Jurkat , Masculino , Micose Fungoide/metabolismo , Fator de Transcrição STAT3/metabolismo , Pele/patologia
11.
Cell Cycle ; 12(12): 1939-47, 2013 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-23676217

RESUMO

The pathogenesis of cutaneous T-cell lymphoma (CTCL) remains elusive. Recent discoveries indicate that the oncogenic microRNA miR-155 is overexpressed in affected skin from CTCL patients. Here, we address what drives the expression of miR-155 and investigate its role in the pathogenesis of CTCL. We show that malignant T cells constitutively express high levels of miR-155 and its host gene BIC (B cell integration cluster). Using ChIP-seq, we identify BIC as a target of transcription factor STAT5, which is aberrantly activated in malignant T cells and induced by IL-2/IL-15 in non-malignant T cells. Incubation with JAK inhibitor or siRNA-mediated knockdown of STAT5 decreases BIC/miR-155 expression, whereas IL-2 and IL-15 increase their expression in cell lines and primary cells. In contrast, knockdown of STAT3 has no effect, and BIC is not a transcriptional target of STAT3, indicating that regulation of BIC/miR-155 expression by STAT5 is highly specific. Malignant proliferation is significantly inhibited by an antisense-miR-155 as well as by knockdown of STAT5 and BIC.   In conclusion, we provide the first evidence that STAT5 drives expression of oncogenic BIC/miR-155 in cancer. Moreover, our data indicate that the STAT5/BIC/miR-155 pathway promotes proliferation of malignant T cells, and therefore is a putative target for therapy in CTCL.


Assuntos
Linfoma Cutâneo de Células T/metabolismo , Fator de Transcrição STAT5/metabolismo , Western Blotting , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Eletroforese em Gel de Poliacrilamida , Citometria de Fluxo , Humanos , Técnicas In Vitro , Linfoma Cutâneo de Células T/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT5/genética
12.
Blood ; 118(22): 5891-900, 2011 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-21865341

RESUMO

Cutaneous T-cell lymphomas (CTCLs) are the most frequent primary skin lymphomas. Nevertheless, diagnosis of early disease has proven difficult because of a clinical and histologic resemblance to benign inflammatory skin diseases. To address whether microRNA (miRNA) profiling can discriminate CTCL from benign inflammation, we studied miRNA expression levels in 198 patients with CTCL, peripheral T-cell lymphoma (PTL), and benign skin diseases (psoriasis and dermatitis). Using microarrays, we show that the most induced (miR-326, miR-663b, and miR-711) and repressed (miR-203 and miR-205) miRNAs distinguish CTCL from benign skin diseases with > 90% accuracy in a training set of 90 samples and a test set of 58 blinded samples. These miRNAs also distinguish malignant and benign lesions in an independent set of 50 patients with PTL and skin inflammation and in experimental human xenograft mouse models of psoriasis and CTCL. Quantitative (q)RT-PCR analysis of 103 patients with CTCL and benign skin disorders validates differential expression of 4 of the 5 miRNAs and confirms previous reports on miR-155 in CTCL. A qRT-PCR-based classifier consisting of miR-155, miR-203, and miR-205 distinguishes CTCL from benign disorders with high specificity and sensitivity, and with a classification accuracy of 95%, indicating that miRNAs have a high diagnostic potential in CTCL.


Assuntos
Perfilação da Expressão Gênica , Linfoma Cutâneo de Células T/diagnóstico , Linfoma Cutâneo de Células T/genética , MicroRNAs/genética , Animais , Células Cultivadas , Feminino , Regulação Leucêmica da Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Camundongos Transgênicos , Análise em Microsséries , Prognóstico , Psoríase/patologia , Transplante Heterólogo
13.
Mol Immunol ; 48(15-16): 2087-93, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21813181

RESUMO

Recently it has become clear that interferon (IFN)-α, a type I interferon produced rapidly in response to infection, not only plays a key role in innate immunity, but also promotes adaptive immune responses by influencing the production or function of other cytokines. During infections IFN-α fosters the production of IL-15, which plays a pivotal role in the development, survival and function of NK cells and recruitment and activation of T cells. Since these two cytokines exert overlapping functions during infections, this investigation was undertaken to study the priming effect of IFN-α on the effect of IL-15 on human T and NK cells. We show that IFN-α induces an increased expression of IL-15Rα in human activated peripheral T cells, and in CD8(+) and CD4(+) T-cell lines. Functionally, the IFN-α-enhanced IL-15Rα expression resulted in an enhanced IL-15-mediated phosphorylation of STAT5 and STAT3 followed by a further increase in IL-15Rα expression. Moreover, IFN-α significantly increased the IL-15-induced cytotoxic activity of freshly isolated T and NK cells. Taken together, our data show that IFN-α boosts signaling and functional effects of IL-15, at least in part by fostering the increased IL-15R expression, thus add new facet to the emerging role of IFN-α as an important primer of adaptive immune responses.


Assuntos
Interferon-alfa/imunologia , Interleucina-15/imunologia , Células Matadoras Naturais/imunologia , Ativação Linfocitária/imunologia , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Western Blotting , Separação Celular , Células Cultivadas , Citotoxicidade Imunológica/imunologia , Citometria de Fluxo , Humanos , Interferon-alfa/metabolismo , Interleucina-15/metabolismo , Células Matadoras Naturais/metabolismo , Teste de Cultura Mista de Linfócitos , Receptores de Interleucina-15/imunologia , Receptores de Interleucina-15/metabolismo , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/metabolismo , Linfócitos T/metabolismo
14.
J Invest Dermatol ; 131(6): 1331-8, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21346774

RESUMO

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 ß 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.


Assuntos
Interleucina-17/fisiologia , Janus Quinase 3/fisiologia , Linfoma Cutâneo de Células T/imunologia , Fator de Transcrição STAT3/fisiologia , Transdução de Sinais/fisiologia , Neoplasias Cutâneas/imunologia , Linhagem Celular Tumoral , Humanos , Interleucina-17/análise , Linfoma Cutâneo de Células T/etiologia , Neoplasias Cutâneas/etiologia , Linfócitos T/imunologia
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