RESUMO
Central hypothyroidism and dyslipidemia are well-known adverse events (AEs) of bexarotene therapy. Although hypothyroidism is known to cause dyslipidemia, no study has examined the association between hypothyroidism and dyslipidemia in patients undergoing bexarotene therapy. The aim of this study is to examine this association. A retrospective observational study was performed among 294 patients who initiated bexarotene therapy in Japan (nation-wide postmarketing complete surveillance). Jonckheere-Terpstra (one sided) test was performed to evaluate the effect of the bexarotene dose on lipid metabolisms, and regression analyses were performed to evaluate associations of bexarotene dose, free thyroxine (FT4), body mass index (BMI), and lipid metabolisms. Most patients developed hypothyroidism. Two-third of patients showed FT4 values below the lower limit at 1 week. Triglycerides (TG) increased in a bexarotene dose-dependent manner, and grade ≥3 AEs on hypertriglyceridemia was observed in 39% of the patients. Additionally, one-third of grade ≥3 AEs on hypertriglyceridemia occurred within 1 week. The delta_FT4 (difference in FT4 from baseline) negatively correlated with TG increase at 1 week (p = 0.012) but not with low density lipoprotein cholesterol (LDL-C) increase at any week. Bexarotene-induced hypothyroidism is almost inevitable and occurred quickly. Bexarotene-induced hypertriglyceridemia showed positive bexarotene dose dependency and negative delta_FT4 dependency. Prophylactic and appropriate thyroid hormone compensation therapy and starting bexarotene at low doses with subsequent titration while managing dyslipidemia may have a beneficial effect for the successful continuation of bexarotene therapy without severe endocrine and metabolic AEs.
Assuntos
Bexaroteno , Dislipidemias , Hipotireoidismo , Humanos , Bexaroteno/efeitos adversos , Hipotireoidismo/induzido quimicamente , Hipotireoidismo/epidemiologia , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso , Dislipidemias/induzido quimicamente , Japão/epidemiologia , Tiroxina/sangue , Triglicerídeos/sangue , Adulto , Tetra-Hidronaftalenos/efeitos adversos , Tetra-Hidronaftalenos/uso terapêutico , Idoso de 80 Anos ou mais , Anticarcinógenos/uso terapêutico , Anticarcinógenos/efeitos adversos , Hipertrigliceridemia/induzido quimicamenteRESUMO
Dysregulation of inflammatory cytokines in keratinocytes promote the pathogenesis of the skin inflammation, such as allergic contact dermatitis (ACD). High-mobility group box 1 protein (HMGB1) has been implicated in the promotion of skin inflammation upon its extracellular release as a damage-associated molecular pattern molecule. However, whether and how HMGB1 in keratinocytes contributes to ACD and other skin disorders remain elusive. In this study, we generated conditional knockout mice in which the Hmgb1 gene is specifically deleted in keratinocytes, and examined its role in ACD models. Interestingly, the mutant mice showed exacerbated skin inflammation, accompanied by increased ear thickening in 2,4-dinitrofluorobenezene-induced ACDs. The mRNA expression of interleukin-24 (IL-24), a cytokine known to critically contribute to ACD pathogenesis, was elevated in skin lesions of the mutant mice. As with constitutively expressed, IL-4-induced Il24 mRNA, expression was also augmented in the Hmgb1-deficient keratinocytes, which would account for the exacerbation of ACD in the mutant mice. Mechanistically, we observed an increased binding of trimethyl histone H3 (lys4) (H3K4me3), a hallmark of transcriptionally active genes, to the promoter region of the Il24 gene in the hmgb1-deficient cells. Thus, the nuclear HMGB1 is a critical "gate keeper" in that the dermal homeostasis is contingent to its function in chromatin remodeling. Our study revealed a facet of nuclear HMGB1, namely its antiinflammatory function in keratinocytes for the skin homeostasis.
Assuntos
Montagem e Desmontagem da Cromatina , Dermatite Alérgica de Contato/metabolismo , Proteína HMGB1/metabolismo , Histonas/metabolismo , Interleucinas/metabolismo , Queratinócitos/metabolismo , Animais , Dermatite Alérgica de Contato/genética , Dermatite Alérgica de Contato/prevenção & controle , Dinitrofluorbenzeno/toxicidade , Modelos Animais de Doenças , Orelha/patologia , Deleção de Genes , Regulação da Expressão Gênica/genética , Proteína HMGB1/deficiência , Proteína HMGB1/genética , Inflamação/genética , Inflamação/metabolismo , Interleucina-4/farmacologia , Interleucinas/genética , Camundongos , Camundongos Knockout , Regiões Promotoras Genéticas , Pele/imunologia , Pele/metabolismo , Pele/patologia , Quimeras de TransplanteRESUMO
BACKGROUND: The clinical implications of DUSP22 rearrangement and the association between DUSP22 rearrangement and lymphoid enhancer-binding factor 1 (LEF1) expression pattern in CD30+ cutaneous T-cell lymphomas (CTCLs) are unknown. OBJECTIVES: This study assessed the incidence of DUSP22 rearrangement and its clinical and immunohistochemical implications in primary cutaneous anaplastic large-cell lymphoma (pcALCL), lymphomatoid papulosis (LyP) and CD30+ mycosis fungoides with large-cell transformation (MF-LCT), focusing especially on the association with the prognosis and LEF1 expression pattern. Prognostic factors of pcALCL were also examined. METHODS: We conducted a multicentre retrospective study including patients with pcALCL, LyP and MF-LCT diagnosed between 1 January 2000 and 31 December 2018 in Japan. Baseline data at diagnosis, treatment course, overall survival (OS) and disease-specific survival (DSS) were collected. Immunohistochemical analysis and fluorescence in situ hybridization to detect DUSP22 and TP63 rearrangement were performed using skin samples at diagnosis. We investigated the association between staining pattern and these gene rearrangements. We also assessed the prognostic implications of clinical status, immunohistochemical results and the presence of gene rearrangements. RESULTS: DUSP22 rearrangement was detected in 50% (11 of 22) of cases of pcALCL, but not in any cases with LyP (0 of 14) or MF-LCT (0 of 11). TP63 rearrangement was not detected in any case. Clinically, patients with pcALCL with DUSP22 rearrangement did not tend to develop ulcers (P = 0.081). There was no significant association between DUSP22 rearrangement status and immunohistochemical results, including LEF1 expression pattern. T3 stage and the presence of lower limb lesions were significantly associated with shorter OS (P = 0.012 and 0.021, respectively, by log-rank test). Similarly, they were significantly correlated with shorter DSS (P = 0.016 and 0.0001, respectively). CONCLUSIONS: DUSP22 rearrangement is relatively specific to pcALCL among CD30+ CTCLs in Japan. Although the LEF1 expression pattern was not related to DUSP22 rearrangement in pcALCL, there was no rearrangement if LEF1 was not expressed. We confirmed that T3 stage and the lower limb involvement were significantly associated with decreased OS and DSS. The presence or absence of lower limb lesions should be included in T-stage subcategorization in the future.
Assuntos
Linfoma Anaplásico de Células Grandes , Papulose Linfomatoide , Micose Fungoide , Neoplasias Cutâneas , Humanos , Linfoma Anaplásico de Células Grandes/diagnóstico , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/patologia , Estudos Retrospectivos , Neoplasias Cutâneas/patologia , Antígeno Ki-1 , Prognóstico , Hibridização in Situ Fluorescente , Japão/epidemiologia , Micose Fungoide/patologiaRESUMO
BACKGROUND: Consensus about the definition and classification of 'plaque' in mycosis fungoides is lacking. OBJECTIVES: To delineate a comprehensive view on how the 'plaque' entity is defined and managed in clinical practice; to evaluate whether the current positioning of plaques in the TNMB classification is adequate. METHODS: A 12-item survey was circulated within a selected panel of 22 experts (pathologists, dermatologists, haematologists and oncologists), members of the EORTC and International Society for Cutaneous Lymphoma. The questionnaire discussed clinical and histopathological definitions of plaques and its relationship with staging and treatment. RESULTS: Total consensus and very high agreement rates were reached in 33.3% of questions, as all panellists regularly check for the presence of plaques, agree to evaluate the presence of plaques as a potential separate T class, and concur on the important distinction between plaque and patch for the management of early-stage MF. High agreement was reached in 41.7% of questions, since more than 50% of the responders use Olsen's definition of plaque, recommend the distinction between thin/thick plaques, and agree on performing a biopsy on the most infiltrated/indurated lesion. High divergence rates (25%) were reported regarding the possibility of a clinically based distinction between thin and thick plaques and the role of histopathology to plaque definition. CONCLUSIONS: The definition of 'plaque' is commonly perceived as a clinical entity and its integration with histopathological features is generally reserved to specific cases. To date, no consensus is achieved as for the exact definition of thin and thick plaques and current positioning of plaques within the TNMB system is considered clinically inadequate. Prospective studies evaluating the role of histopathological parameters and other biomarkers, as well as promising diagnostic tools, such as US/RM imaging and high-throughput blood sequencing, are much needed to fully integrate current clinical definitions with more objective parameters.
Assuntos
Linfoma Cutâneo de Células T , Micose Fungoide , Neoplasias Cutâneas , Humanos , Estudos Prospectivos , Micose Fungoide/patologia , Linfoma Cutâneo de Células T/patologia , Neoplasias Cutâneas/patologia , BiópsiaRESUMO
While atopic dermatitis (AD) is considered as a T helper 2 (Th2)-centered disease, an increase in other types of inflammatory cytokines is also noted in AD and they may also contribute to the development of the disease. Recently, the efficacy of an anti-IL-36 receptor antibody in AD was demonstrated in a clinical trial. Although there have been several reports on IL-36α and IL-36γ expression and function in AD, IL-36ß has been barely studied. In this report, we examined IL-36ß expression and function using clinical samples of AD and the epidermal keratinocyte cell line, HaCaT cells. We demonstrated that IL-36ß expression in epidermal keratinocytes was increased in AD lesional skin compared to healthy skin. IL-36ß promoted vascular endothelial growth factor A production in HaCaT keratinocytes through phosphorylation of extracellular signal-regulated kinases 1 and 2. In addition, IL-36ß up-regulated placental growth factor mRNA expression in HaCaT keratinocytes. IL-36ß expression levels in epidermal keratinocytes were correlated with the number of dermal vessels in AD skin. These results suggest that IL-36ß may play an important role for angiogenesis in lesional skin of AD and that IL-36ß can be a therapeutic target in AD.
Assuntos
Dermatite Atópica , Interleucina-1 , Humanos , Dermatite Atópica/metabolismo , População do Leste Asiático , Queratinócitos/metabolismo , Fator de Crescimento Placentário/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Interleucina-1/genética , Interleucina-1/metabolismo , Células HaCaTRESUMO
E7777 is a recombinant cytotoxic fusion protein composed of the diphtheria toxin fragments A and B and human interleukin-2. It shares an amino acid sequence with denileukin diftitox, but has improved purity and an increased percentage of active monomer. We undertook a multicenter, single-arm phase II study of E7777 in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) to evaluate its efficacy, safety, pharmacokinetics, and immunogenicity. A total of 37 patients were enrolled, of which 17 and 19 patients had PTCL and CTCL, respectively, and one patient with another type of lymphoma (extranodal natural killer/T-cell lymphoma, nasal type), diagnosed by the Central Pathological Diagnosis Committee. Among the 36 patients with PTCL and CTCL, objective response rate based on the independent review was 36% (41% and 31%, respectively). The median progression-free survival was 3.1 months (2.1 months in PTCL and 4.2 months in CTCL). The common adverse events (AEs) observed were increased aspartate aminotransferase (AST) / alanine aminotransferase (ALT), hypoalbuminemia, lymphopenia, and pyrexia. Our results indicated that a 9 µg/kg/d dose of E7777 shows efficacy and a manageable safety profile in Japanese patients with relapsed or refractory PTCL and CTCL, with clinical activity observed across the range of CD25 expression. The common AEs were manageable, but increase in ALT / AST, hypoalbuminemia, and capillary leak syndrome should be carefully managed during the treatment.
Assuntos
Interleucina-2/administração & dosagem , Linfoma Cutâneo de Células T/tratamento farmacológico , Linfoma de Células T Periférico/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Proteínas Recombinantes de Fusão/administração & dosagem , Administração Intravenosa , Sítios de Ligação , Toxina Diftérica/administração & dosagem , Toxina Diftérica/efeitos adversos , Toxina Diftérica/química , Toxina Diftérica/genética , Toxina Diftérica/farmacocinética , Esquema de Medicação , Feminino , Humanos , Interleucina-2/efeitos adversos , Interleucina-2/química , Interleucina-2/genética , Interleucina-2/farmacocinética , Japão , Linfoma Cutâneo de Células T/sangue , Linfoma de Células T Periférico/sangue , Masculino , Recidiva Local de Neoplasia/sangue , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/farmacocinética , Análise de Sobrevida , Resultado do TratamentoRESUMO
OPINION STATEMENT: While most patients with early-stage mycosis fungoides (MF) follow an indolent course, patients with advanced-stage MF/Sézary syndrome (SS) have a poor prognosis with a median survival of less than 5 years. Although there are a number of treatments currently available, achieving and maintaining a durable response remain challenging, especially in advanced-stage MF/SS. The choice of frontline therapy is dependent on the stage of disease. For early-stage MF, the treatment concept is to control skin lesions mainly by skin-directed therapies, such as topical therapies, phototherapies, and radiotherapies. For advanced-stage MF/SS, systemic treatments by biological or targeted therapies including bexarotene and interferon either alone or in combination are tried first, with more immunosuppressive chemotherapies being reserved for refractory or rapidly progressive disease. Recent improvements in biological or targeted therapies include brentuximab vedotin and mogamulizumab. When biopsy samples have 10% or more CD30-positive malignant cells, brentuximab vedotin, an anti-CD30 antibody conjugated to monomethyl auristin E, can be a desirable treatment option. For cases with blood involvement, mogamulizumab, an antibody binding to C-C chemokine receptor 4, is effective with high response rates. In the refractory setting, alemtuzumab, histone deacetylase inhibitors, pralatrexate, gemcitabine, and doxorubicin are considered as the treatment option. Because only allogeneic hematopoietic stem cell transplantation can offer a chance of cure with durable complete remission, advanced-stage patients with a markedly short life expectancy should be evaluated for eligibility. Given that there are few randomized controlled studies in the literature, it is necessary to investigate which therapy is preferable for each patient with MF/SS by comparative prospective trials.
Assuntos
Micose Fungoide/terapia , Síndrome de Sézary/terapia , Neoplasias Cutâneas/terapia , Tomada de Decisão Clínica , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Gerenciamento Clínico , Progressão da Doença , Humanos , Micose Fungoide/diagnóstico , Micose Fungoide/etiologia , Micose Fungoide/mortalidade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Síndrome de Sézary/diagnóstico , Síndrome de Sézary/etiologia , Síndrome de Sézary/mortalidade , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/mortalidade , Resultado do TratamentoRESUMO
Mycosis fungoides (MF) and Sézary syndrome (SS), the most common types of cutaneous T-cell lymphoma (CTCL), are characterized by proliferation of mature CD4+ T-helper cells. Patients with advanced-stage MF and SS have poor prognosis, with 5-year survival rates of 52%. Although a variety of systemic therapies are currently available, there are no curative options for such patients except for stem cell transplantation, and thus the treatment of advanced MF and SS still remains challenging. Therefore, elucidation of the pathophysiology of MF/SS and development of medical treatments are desired. In this study, we focused on a molecule called OX40. We examined OX40 and OX40L expression and function using clinical samples of MF and SS and CTCL cell lines. OX40 and OX40L were co-expressed on tumor cells of MF and SS. OX40 and OX40L expression was increased and correlated with disease severity markers in MF/SS patients. Anti-OX40 antibody and anti-OX40L antibody suppressed the proliferation of CTCL cell lines both in vitro and in vivo. These results suggest that OX40-OX40L interactions could contribute to the proliferation of MF/SS tumor cells and that the disruption of OX40-OX40L interactions could become a new therapeutic strategy for the treatment of MF/SS.
Assuntos
Antígenos de Diferenciação/genética , Linfoma Cutâneo de Células T/tratamento farmacológico , Micose Fungoide/tratamento farmacológico , Ligante OX40/genética , Síndrome de Sézary/tratamento farmacológico , Anticorpos Anti-Idiotípicos/imunologia , Anticorpos Anti-Idiotípicos/farmacologia , Antígenos de Diferenciação/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Linfoma Cutâneo de Células T/genética , Linfoma Cutâneo de Células T/imunologia , Linfoma Cutâneo de Células T/patologia , Micose Fungoide/genética , Micose Fungoide/imunologia , Micose Fungoide/patologia , Ligante OX40/antagonistas & inibidores , Síndrome de Sézary/genética , Síndrome de Sézary/imunologia , Síndrome de Sézary/patologiaRESUMO
The incidence of cancers in atopic dermatitis (AD) is not increased, although the Th2-dominant environment is known to downregulate tumor immunity. To gain mechanistic insights regarding tumor immunity in AD, we utilized CCL17 transgenic (TG) mice overexpressing CCL17, which is a key chemokine in AD. Tumor formation and lung metastasis were accelerated in CCL17 TG mice when melanoma cells were injected subcutaneously or intravenously. Flow cytometric analysis showed increases in regulatory T cells (Tregs) in lymph nodes in CCL17 TG mice with high mRNA levels of IL-10 and Foxp3 in tumors, suggesting that Tregs attenuated tumor immunity. The frequency of myeloid-derived suppressor cells (MDSCs), however, was significantly decreased in tumors of CCL17 TG mice, suggesting that decreased MDSCs might promote tumor immunity. Expression of CXCL17, a chemoattractant of MDSCs, was decreased in tumors of CCL17 TG mice. Depletion of Tregs by the anti-CD25 antibody markedly reduced tumor volumes in CCL17 TG mice, suggesting that tumor immunity was accelerated by the decrease in MDSCs in the absence of Tregs. Thus, CCL17 attenuates tumor immunity by increasing Tregs and Th2 cells, while it decreases MDSCs through reductions in CXCL17, which may work as a "safety-net" to reduce the risk of malignant tumors in the Th2-dominant environment.
Assuntos
Quimiocina CCL17/metabolismo , Dermatite Atópica/imunologia , Células Supressoras Mieloides/imunologia , Neoplasias/epidemiologia , Neoplasias/imunologia , Linfócitos T Reguladores/imunologia , Animais , Fatores Quimiotáticos/farmacologia , Regulação para Baixo/efeitos dos fármacos , Humanos , Imunidade , Incidência , Neoplasias Pulmonares/secundário , Camundongos Transgênicos , Modelos Biológicos , Neoplasias Cutâneas/patologia , Células Th2/efeitos dos fármacos , Células Th2/imunologiaRESUMO
CD147, a transmembrane glycoprotein that belongs to the immunoglobulin superfamily, and cyclophilin A (CypA), one of the binding partners of CD147, are overexpressed in tumor cells and associated with the progression of several malignancies, including both solid and hematological malignancies. However, CD147 and CypA involvement in cutaneous T-cell lymphoma (CTCL) has not been reported. In this study, we examined CD147 and CypA expression and function using clinical samples of mycosis fungoides (MF) and Sézary syndrome (SS) and CTCL cell lines. CD147 and CypA were overexpressed by tumor cells of MF/SS, and CypA was also expressed by epidermal keratinocytes in MF/SS lesional skin. Serum CypA levels were increased and correlated with disease severity markers in MF/SS patients. Anti-CD147 antibody and/or anti-CypA antibody suppressed the proliferation of CTCL cell lines, both in vitro and in vivo, via downregulation of phosphorylated extracellular-regulated kinase 1/2 and Akt. These results suggest that CD147-CypA interactions can contribute to the proliferation of MF/SS tumor cells in both a autocrine and paracrine manner, and that the disruption of CD147-CypA interactions could be a new therapeutic strategy for the treatment of MF/SS.
Assuntos
Basigina/metabolismo , Proliferação de Células , Ciclofilina A/metabolismo , Linfoma Cutâneo de Células T/patologia , Micose Fungoide/patologia , Síndrome de Sézary/patologia , Neoplasias Cutâneas/patologia , Basigina/genética , Estudos de Casos e Controles , Ciclofilina A/genética , Feminino , Humanos , Linfoma Cutâneo de Células T/genética , Linfoma Cutâneo de Células T/metabolismo , Masculino , Pessoa de Meia-Idade , Micose Fungoide/genética , Micose Fungoide/metabolismo , Índice de Gravidade de Doença , Síndrome de Sézary/genética , Síndrome de Sézary/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismoRESUMO
CD137 and its ligand, CD137L, are expressed on activated T cells and antigen-presenting cells, respectively. Recent studies have shown that CD137L and CD137 are aberrantly expressed by tumor cells, especially in some hematopoietic malignancies, and interactions between these molecules on tumor cells promote tumor growth. In this study, we investigated the roles of CD137L and CD137 in cutaneous T-cell lymphoma (CTCL), represented by mycosis fungoides and Sézary syndrome. Flow cytometric analysis showed that primary Sézary cells and CTCL cell lines (Hut78, MyLa, HH, SeAx, and MJ) aberrantly expressed CD137L. CD137L expression by tumor cells in CTCL was also confirmed by immunohistochemistry. Anti-CD137L-neutralizing antibody inhibited proliferation, survival, CXCR4-mediated migration, and in vivo growth in CTCL cell lines through inhibition of phosphorylation of AKT, extracellular signal-regulated kinase 1/2, p38 MAPK, and JNK. Moreover, suppression of CD137L signaling decreased antiapoptotic proteins Bcl-2 and phosphorylated Bad. We also explored the transcription factor regulating CD137L expression. Because GATA6 has been proposed as an oncogene in many types of tumors with aberrant CD137L expression, we examined GATA6 expression and the involvement of GATA6 in CD137L expression in CTCL. DNA hypomethylation and histone acetylation induced GATA6 overexpression in CTCL cells. Furthermore, chromatin immunoprecipitation, luciferase reporter assay, and knockdown by short hairpin RNA showed that GATA6 directly upregulated CD137L expression. Inhibition of GATA6 resulted in decreased survival and in vivo growth in CTCL cells. Collectively, our findings prompt a novel therapeutic approach to CTCL based on the discovery that the GATA6/CD137L axis plays an important role in the tumorigenesis of CTCL.
Assuntos
Ligante 4-1BB/genética , Fator de Transcrição GATA6/genética , Regulação Neoplásica da Expressão Gênica , Linfoma Cutâneo de Células T/genética , Neoplasias Cutâneas/genética , Regulação para Cima , Ligante 4-1BB/análise , Adulto , Idoso , Movimento Celular , Proliferação de Células , Metilação de DNA , Progressão da Doença , Epigênese Genética , Feminino , Fator de Transcrição GATA6/análise , Humanos , Linfoma Cutâneo de Células T/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Cutâneas/patologiaRESUMO
In many malignancies, dysregulation of the Notch pathways, composed of 4 Notch receptors (Notch1-4) and 5 Notch ligands (Jagged1-2, Delta-like ligand-1, 3-4), is associated with their development. In mycosis fungoides, interaction between Notch1 and Jagged1 is known to activate the Notch pathways and promote the proliferation of tumour cells. However, the involvement of other Notch ligands has not been reported. This study investigated the roles of Delta-like ligand 4 in mycosis fungoides. Delta-like ligand 4 mRNA levels in lesional skin of patients with mycosis fungoides were significantly elevated compared with those of normal controls, and correlated with disease-specific mortality. Immunohistochemical staining demonstrated prominent expression of Delta-like ligand 4 on vascular endothelial cells and tumour cells in mycosis fungoides lesional skin. In addition, Delta-like ligand 4 augmented the proliferation of cutaneous T-cell lym-phoma cell lines. These results suggest that enhanced Delta-like ligand 4 expression may contribute directly to the progression of mycosis fungoides through proliferating tumour cells.
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Micose Fungoide/metabolismo , Neoplasias Cutâneas/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Micose Fungoide/patologia , Estadiamento de Neoplasias , Neoplasias Cutâneas/patologiaRESUMO
Interferon regulatory factors (IRFs) play diverse roles in the regulation of the innate and adaptive immune responses in various diseases. In psoriasis, IRF2 is known to be involved in pathogenesis, while studies on other IRFs are limited. In this study, we investigated the role of IRF5 in psoriasis using imiquimod-induced psoriasis-like dermatitis. Although IRF5 is known to play a critical role in the induction of proinflammatory cytokines by immune cells, such as dendritic cells (DCs), macrophages, and monocytes, IRF5 deficiency unexpectedly exacerbated psoriasiform skin inflammation. The interferon-α and tumor necrosis factor-α mRNA expression levels were decreased, while levels of Th17 cytokines including IL-17, IL-22, and IL-23 were increased in IRF5-deficient mice. Furthermore, IL-23 expression in DCs from IRF5-deficient mice was upregulated both in steady state and after toll-like receptor 7/8 agonist stimulation. Importantly, the expression of IRF4, which is also important for the IL-23 production in DCs, was augmented in DCs from IRF5-deficient mice. Taken together, our results suggest that IRF5 deficiency induces the upregulation of IRF4 in DCs followed by augmented IL-23 production, resulting in the amplification of Th17 responses and the exacerbation of imiquimod-induced psoriasis-like skin inflammation. The regulation of IRF4 or IRF5 expression may be a novel therapeutic approach to psoriasis.
Assuntos
Fatores Reguladores de Interferon/genética , Interleucinas/metabolismo , Psoríase/metabolismo , Animais , Células Cultivadas , Células Dendríticas/metabolismo , Feminino , Imiquimode/toxicidade , Indutores de Interferon/toxicidade , Fatores Reguladores de Interferon/deficiência , Fatores Reguladores de Interferon/metabolismo , Interferons/genética , Interferons/metabolismo , Interleucinas/genética , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/metabolismo , Psoríase/etiologia , Psoríase/genética , Pele/efeitos dos fármacos , Pele/metabolismo , Células Th17/metabolismoRESUMO
Emerging evidence has demonstrated that Toll-like receptors (TLRs) are associated with autoimmune diseases. In this study, we investigated the role of TLR2 in psoriasis using imiquimod-induced psoriasis-like dermatitis. Although TLR2 signaling is known to play a critical role in the induction of proinflammatory cytokines by immune cells, such as dendritic cells (DCs), macrophages, and monocytes, TLR2 deficiency unexpectedly exacerbated psoriasiform skin inflammation. Importantly, messenger RNA (mRNA) levels of Foxp-3 and IL-10 in the lesional skin were significantly decreased in TLR2 KO mice compared with wild-type mice. Furthermore, flow cytometric analysis of the lymph nodes revealed that the frequency of regulatory T cells (Tregs) among CD4-positive cells was decreased. Notably, stimulation with Pam3CSK4 (TLR2/1 ligand) or Pam2CSK4 (TLR2/6 ligand) increased IL-10 production from Tregs and DCs and the proliferation of Tregs. Finally, adoptive transfer of Tregs from wild-type mice reduced imiquimod-induced skin inflammation in TLR2 KO mice. Taken together, our results suggest that TLR2 signaling directly enhances Treg proliferation and IL-10 production by Tregs and DCs, suppressing imiquimod-induced psoriasis-like skin inflammation. Enhancement of TLR2 signaling may be a new therapeutic strategy for psoriasis.
Assuntos
Imiquimode/efeitos adversos , Interleucina-10 , Psoríase , Pele , Linfócitos T Reguladores , Receptor 2 Toll-Like/deficiência , Animais , Imiquimode/farmacologia , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Interleucina-10/genética , Interleucina-10/imunologia , Camundongos , Camundongos Knockout , Psoríase/induzido quimicamente , Psoríase/genética , Psoríase/imunologia , Psoríase/patologia , Pele/imunologia , Pele/patologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Receptor 2 Toll-Like/imunologiaRESUMO
CX3CL1 can function as both an adhesion molecule and a chemokine for CX3CR1+ cells, such as T cells, monocytes, and NK cells. Recent studies have demonstrated that CX3CL1-CX3CR1 interaction is associated with the development of various inflammatory skin diseases. In this study, we examined CX3CR1 involvement in 2,4-dinitrofluorobenzene (DNFB)-induced contact hypersensitivity using CX3CR1-/- mice. Ear swelling and dermal edema were attenuated after DNFB challenge in CX3CR1-/- mice. Expression of TNF-α, IL-6, and M1 macrophage markers was decreased in the ears of CX3CR1-/- mice, whereas expression of M2 macrophage markers including arginase-1 was increased. Decreased TNF-α and IL-6 expression and increased arginase-1 expression were found in peritoneal macrophages from CX3CR1-/- mice. Furthermore, ear swelling was attenuated by depleting dermal macrophages in wild-type mice to a similar level to CX3CR1-/- mice. These results suggest that CX3CR1 deficiency could induce skewed polarization towards M2 phenotype in macrophages, resulting in attenuation of contact hypersensitivity response.
Assuntos
Receptor 1 de Quimiocina CX3C/deficiência , Dermatite de Contato/etiologia , Dermatite de Contato/metabolismo , Dinitrofluorbenzeno/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/fisiologia , Animais , Biomarcadores , Receptor 1 de Quimiocina CX3C/metabolismo , Dermatite de Contato/patologia , Modelos Animais de Doenças , Suscetibilidade a Doenças , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Infiltração de Neutrófilos/imunologiaRESUMO
CXCL17 is expressed in a variety of cancers and promotes tumor progression by recruiting myeloid-derived suppressor cells (MDSCs). MDSCs suppress tumor immunity by attracting regulatory T cells (Tregs) into tumor sites through CCL5. In this study, we examined the role of CXCL17 in skin disorders. CXCL17 mRNA levels in psoriasis skin, but not in lesional skin of atopic dermatitis or cutaneous T cell lymphoma, were significantly higher than those in normal skin. CXCL17 was mainly expressed in the epidermis, and IFN-γ dose-dependently increased CXCL17 expression by human keratinocytes in vitro. As CXCL17 mRNA expression was increased by treatment with imiquimod (IMQ), we examined the effects of CXCL17 in IMQ-induced psoriasis-like skin inflammation. Injection of recombinant CXCL17 into the ear before and during IMQ application decreased ear thickness, inflammatory cytokine expression, and the number of infiltrating cells compared with PBS injection. Flow cytometric analysis and immunofluorescent staining revealed that the numbers of MDSCs, which are CD11b+Gr-1+, and that of Tregs, which are CD4+CD25+, were higher in the ear of the CXCL17-injected mice than in PBS-injected mice. MDSCs, but not Tregs, showed chemotaxis to CXCL17 in vitro. When mice were injected with anti-CCL5 Ab or anti-CCL4 Ab simultaneously with recombinant CXCL17, ear thickness and cytokine expression increased to a similar level of mice treated with PBS and control IgG, suggesting that these chemokines were important for anti-inflammatory effects. Taken together, CXCL17 attenuates IMQ-induced psoriasis-like skin inflammation by recruiting MDSCs and Tregs, which may be important for regulating excessive inflammation in psoriasis skin.
Assuntos
Aminoquinolinas/farmacologia , Quimiocinas CXC/imunologia , Quimiocinas/imunologia , Células Supressoras Mieloides/fisiologia , Pele/efeitos dos fármacos , Pele/imunologia , Linfócitos T Reguladores/imunologia , Animais , Quimiocina CCL4/imunologia , Quimiocina CCL5/imunologia , Quimiocinas/genética , Quimiotaxia , Citocinas/genética , Citocinas/imunologia , Dermatite/tratamento farmacológico , Dermatite/imunologia , Epiderme/efeitos dos fármacos , Epiderme/imunologia , Humanos , Imiquimode , Queratinócitos/efeitos dos fármacos , Queratinócitos/imunologia , Camundongos , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/imunologia , Psoríase/tratamento farmacológico , Psoríase/imunologia , Pele/patologia , Linfócitos T Reguladores/efeitos dos fármacosRESUMO
Tumor cells in cutaneous T-cell lymphoma express limited numbers of chemokine receptors. We investigated the expression patterns of CXCR3, CCR3, CCR4 and CCR10 in mycosis fungoides, Sézary syndrome, lym-phomatoid papulosis and anaplastic large cell lymphoma in 121 skin biopsy samples. CXCR3 was expressed in 86% of mycosis fungoides cases but in no anaplastic large cell lymphoma cases. CCR3 was expressed in 73% of cases of CD30+ lymphoproliferative disorders such as lymphomatoid papulosis and anaplastic large cell lymphoma. Mycosis fungoides/Sézary syndrome patients with high CCR3 or CCR4 expression had a poorer survival prognosis than mycosis fungoides/Sézary syndrome patients whose tumor cells did not express these receptors. CCR10 was expressed in 50% of mycosis fungoides/Sézary syndrome cases and in 13% of cases with CD30+ lym-phoproliferative disorders. These results suggest that differential patterns of CXCR3, CCR3, CCR4 and CCR10 expression are useful for the diagnosis of cutaneous T-cell lymphoma. Moreover, expression of CCR3 or CCR4 suggests a poor prognosis in mycosis fungoides/Sézary syndrome.
Assuntos
Biomarcadores Tumorais/análise , Micose Fungoide/imunologia , Receptores CCR3/análise , Receptores CCR4/análise , Síndrome de Sézary/imunologia , Neoplasias Cutâneas/imunologia , Humanos , Micose Fungoide/mortalidade , Micose Fungoide/patologia , Prognóstico , Receptores CCR10/análise , Receptores CXCR3/análise , Síndrome de Sézary/mortalidade , Síndrome de Sézary/patologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Regulação para CimaRESUMO
OBJECTIVE: This study aimed to examine the superiority of peroxidase detection of macroscopic observations using rat wounds, and to test the external validity of the peroxidase analysis in pressure ulcers (PU) in humans. METHOD: In the animal study, rat wounds were analysed. A cross-sectional study analysed, by wound blotting, exudate samples from full-thickness PUs. Peroxidase activity was divided into two groups (ring and non-ring signals). Scores in the 'inflammation/infection' and 'necrotic tissue' components of DESIGN, a classification tool of PUs, were compared between the groups. RESULTS: In the animal study, 20 rat wounds were assessed and in the clinical study, 62 samples were collected from 26 full-thickness PUs of 21 patients aged ≥ 65 years. In the animal study, five of six wounds with clinical inflammation signs showed ring signal (defined as a signal on the wound edge and no signal on the wound bed). While the tissue sections of three wounds with a ring signal showed inflammatory features, they showed no clinical signs of 'inflammation/infection'. In the clinical study, which analysed 630 ring and 32 non-ring signals, 13 samples in the ring signal group and five in the non-ring signal group had 'inflammation/infection; scores of ≥1 (p=0.016). Despite having no clinical signs, 17 samples showed the ring signal. CONCLUSION: This study revealed the external validity of the wound blotting analysis of peroxidase and demonstrated its use to detect subclinical inflammation.