RESUMO
BACKGROUND: Interleukin (IL)-25 is a member of the IL-17 family, which can promote and augment T-helper (Th) type 2 responses. The expression of IL-25 and its cognate receptor, IL-25 receptor (IL-25R), is upregulated and correlated with disease activity in Th2-associated diseases. OBJECTIVES: To examine the expression and function of IL-25 in cutaneous T-cell lymphoma (CTCL). METHODS: Expression and location of IL-25 in lesional skin was investigated with immunohistochemistry. The effect of various cytokines on IL-25 production from normal human epidermal keratinocytes was assessed by quantitative reverse-transcription real-time polymerase chain reaction. Serum IL-25 levels were measured by enzyme-linked immunosorbent assay. The direct effect of IL-25 on tumour cells was also examined using CTCL cell lines and peripheral blood mononuclear cells in patients with Sézary syndrome. RESULTS: IL-25 expression was increased in epidermal keratinocytes in lesional skin of CTCL. Th2 cytokines, IL-4 and IL-13, and periostin induced IL-25 expression by normal human epidermal keratinocytes. Serum IL-25 levels were increased in patients with advanced CTCL and correlated with serum lactate dehydrogenase levels. MyLa cells expressed IL-25R and its expression was augmented by stimulation with IL-25. IL-25 enhanced IL-13 production from MyLa cells via phosphorylation of signal transducer and activator of transcription 6. Peripheral blood mononuclear cells from one patient with Sézary syndrome expressed IL-25R and showed increase of IL-13 production by IL-25. CONCLUSIONS: Th2 cytokines highly expressed in CTCL lesional skin induce IL-25 production by epidermal keratinocytes, which may, in turn, lead to formation of a Th2-dominant microenvironment through the direct induction of IL-13 by tumour cells.
Assuntos
Interleucina-17/fisiologia , Linfoma Cutâneo de Células T/imunologia , Células Th2/imunologia , Microambiente Tumoral/imunologia , Linhagem Celular , Progressão da Doença , Feminino , Humanos , Interleucina-13/biossíntese , Interleucina-17/metabolismo , Queratinócitos/imunologia , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Fosforilação/imunologia , Receptores de Interleucina/imunologia , Fator de Transcrição STAT6/metabolismo , Regulação para Cima/imunologiaRESUMO
BACKGROUND: Advanced-stage mycosis fungoides (MF)/Sézary syndrome (SS) patients are weighted by an unfavorable prognosis and share an unmet clinical need of effective treatments. International guidelines are available detailing treatment options for the different stages but without recommending treatments in any particular order due to lack of comparative trials. The aims of this second CLIC study were to retrospectively analyze the pattern of care worldwide for advanced-stage MF/SS patients, the distribution of treatments according to geographical areas (USA versus non-USA), and whether the heterogeneity of approaches has potential impact on survival. PATIENTS AND METHODS: This study included 853 patients from 21 specialist centers (14 European, 4 USA, 1 each Australian, Brazilian, and Japanese). RESULTS: Heterogeneity of treatment approaches was found, with up to 24 different modalities or combinations used as first-line and 36% of patients receiving four or more treatments. Stage IIB disease was most frequently treated by total-skin-electron-beam radiotherapy, bexarotene and gemcitabine; erythrodermic and SS patients by extracorporeal photochemotherapy, and stage IVA2 by polychemotherapy. Significant differences were found between USA and non-USA centers, with bexarotene, photopheresis and histone deacetylase inhibitors most frequently prescribed for first-line treatment in USA while phototherapy, interferon, chlorambucil and gemcitabine in non-USA centers. These differences did not significantly impact on survival. However, when considering death and therapy change as competing risk events and the impact of first treatment line on both events, both monochemotherapy (SHR = 2.07) and polychemotherapy (SHR = 1.69) showed elevated relative risks. CONCLUSION: This large multicenter retrospective study shows that there exist a large treatment heterogeneity in advanced MF/SS and differences between USA and non-USA centers but these were not related to survival, while our data reveal that chemotherapy as first treatment is associated with a higher risk of death and/or change of therapy and thus other therapeutic options should be preferable as first treatment approach.
Assuntos
Micose Fungoide/terapia , Síndrome de Sézary/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Austrália/epidemiologia , Brasil/epidemiologia , Criança , Europa (Continente)/epidemiologia , Feminino , Humanos , Japão/epidemiologia , Masculino , Oncologia/métodos , Oncologia/estatística & dados numéricos , Pessoa de Meia-Idade , Micose Fungoide/mortalidade , Micose Fungoide/patologia , Estadiamento de Neoplasias , Estudos Retrospectivos , Síndrome de Sézary/mortalidade , Síndrome de Sézary/patologia , Estados Unidos/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Endothelial protein C receptor (EPCR), expressed predominantly on endothelial cells, plays a critical role in the regulation of the coagulation system and also mediates various cytoprotective effects by binding and activating protein C. So far, the role of EPCR has not been studied in systemic sclerosis (SSc). OBJECTIVES: To investigate the potential contribution of EPCR to the development of SSc. METHODS: EPCR expression was examined in skin samples and cultivated dermal microvascular endothelial cells by immunostaining, immunoblotting and/or quantitative reverse-transcription polymerase chain reaction. Fli1, binding to the PROCR promoter, was assessed by chromatin immunoprecipitation. Serum EPCR levels were determined by enzyme-linked immunosorbent assay in 65 patients with SSc and 20 healthy subjects. RESULTS: EPCR expression was decreased in dermal small vessels of SSc lesional skin compared with those of healthy control skin. Transcription factor Fli1, deficiency of which is implicated in SSc vasculopathy, occupied the PROCR promoter, and EPCR expression was suppressed in Fli1 small interfering RNA-treated endothelial cells and dermal small vessels of Fli1(+/-) mice. In patients with SSc, decreased serum EPCR levels were associated with diffuse skin involvement, interstitial lung disease and digital ulcers. Furthermore, serum EPCR levels inversely correlated with plasma levels of plasmin-α2-plasmin inhibitor complex (PIC). Importantly, bosentan significantly reversed circulating EPCR and PIC levels in patients with SSc, and the expression of Fli1 and EPCR in dermal small vessels was elevated in patients treated with bosentan compared with untreated patients. CONCLUSIONS: Endothelial EPCR downregulation due to Fli1 deficiency may contribute to hypercoagulation status leading to tissue fibrosis and impaired peripheral circulation in SSc.
Assuntos
Antígenos CD/fisiologia , Proteína Proto-Oncogênica c-fli-1/deficiência , Receptores de Superfície Celular/fisiologia , Escleroderma Sistêmico/etiologia , Adulto , Idoso , Análise de Variância , Animais , Bleomicina/farmacologia , Bosentana , Estudos de Casos e Controles , Células Cultivadas , Regulação para Baixo/fisiologia , Células Endoteliais/metabolismo , Receptor de Proteína C Endotelial , Antagonistas dos Receptores de Endotelina/farmacologia , Endotélio Vascular/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Fibrinolisina/efeitos dos fármacos , Humanos , Masculino , Camundongos , Microvasos/metabolismo , Pessoa de Meia-Idade , Escleroderma Sistêmico/sangue , Sulfonamidas/farmacologia , Trombofilia/etiologia , alfa 2-Antiplasmina/efeitos dos fármacosRESUMO
BACKGROUND: LL-37 is an antimicrobial peptide with pleiotropic effects on the immune system, angiogenesis and tissue remodelling. These are cardinal pathological events in systemic sclerosis (SSc). OBJECTIVES: To elucidate the potential role of LL-37 in SSc. METHODS: The expression of target molecules was evaluated by immunostaining and quantitative reverse-transcription real-time polymerase chain reaction in human and murine skin. The mechanisms regulating LL-37 expression in endothelial cells were examined by gene silencing and chromatin immunoprecipitation. Serum LL-37 levels were determined by enzyme-linked immunosorbent assay. RESULTS: In SSc lesional skin, LL-37 expression was increased in dermal fibroblasts, perivascular inflammatory cells, keratinocytes and, particularly, dermal small vessels. Expression positively correlated with interferon-α expression, possibly reflecting LL-37-dependent induction of interferon-α. In SSc animal models, bleomycin-treated skin exhibited the expression pattern of CRAMP, a murine homologue of LL-37, similar to that of LL-37 in SSc lesional skin. Furthermore, Fli1+/- mice showed upregulated expression of CRAMP in dermal small vessels. Fli1 binding to the CAMP (LL-37 gene) promoter and Fli1 deficiency-dependent induction of LL-37 were also confirmed in human dermal microvascular endothelial cells. In the analysis of sera, patients with SSc had serum LL-37 levels significantly higher than in healthy controls. Furthermore, serum LL-37 levels positively correlated with skin score and the activity of alveolitis and were significantly elevated in patients with digital ulcers compared with those without. CONCLUSIONS: LL-37 upregulation, induced by Fli1 deficiency at least in endothelial cells, potentially contributes to the development of skin sclerosis, interstitial lung disease and digital ulcers in SSc.
Assuntos
Catelicidinas/fisiologia , Escleroderma Sistêmico/etiologia , Pele/patologia , Doenças Vasculares/etiologia , Adulto , Idoso , Animais , Peptídeos Catiônicos Antimicrobianos/metabolismo , Catelicidinas/metabolismo , Células Endoteliais/metabolismo , Feminino , Fibrose/sangue , Fibrose/etiologia , Humanos , Interferon-alfa/metabolismo , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Proteína Proto-Oncogênica c-fli-1/deficiência , Escleroderma Sistêmico/sangue , Regulação para Cima/fisiologia , Doenças Vasculares/sangueRESUMO
BACKGROUND: Interleukin (IL)-33 is a recently identified cytokine, which is a member of the IL-1 family and binds to a heterodimeric receptor comprising ST2 (suppression of tumorigenicity 2) and IL-1 receptor accessory protein. Serum levels of IL-33 have been reported to be upregulated in various T helper (Th)1/Th17-mediated diseases, such as rheumatoid arthritis and inflammatory bowel disease. IL-33 expression is increased in lesional skin in patients with psoriasis, but serum levels in patients with psoriasis have not yet been studied. AIM: To study serum IL-33 levels in patients with psoriasis, a Th1/Th17-mediated skin disease, before and after anti-tumour necrosis factor (TNF)-α therapy. METHODS: Serum IL-33 levels were measured in patients with psoriasis vulgaris (PV), psoriatic arthritis (PsA) or pustular psoriasis (PP), and compared with those of healthy controls. Associations between serum IL-33 levels and serum TNF-α, IL-6, vascular endothelial growth factor and C-reactive protein levels were also studied. In addition, the effect of IL-33 stimulation on IL-6, IL-8, TNF-α and VEGF secretion by human keratinocyte was analysed. RESULTS: Serum IL-33 levels in patients with PV, PsA and PP were significantly higher than those in healthy controls. Serum IL-33 levels correlated with serum TNF-α levels in patients with psoriasis, and decreased after anti-TNF-α therapy. IL-33 stimulated IL-6 and IL-8 secretion by human keratinocytes. CONCLUSIONS: These results suggest that serum IL-33 levels generally reflect increased inflammation in patients with psoriasis.
Assuntos
Interleucina-33/metabolismo , Psoríase/metabolismo , Adulto , Análise de Variância , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Citocinas/metabolismo , Feminino , Humanos , Interleucinas/metabolismo , Queratinócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Psoríase/sangue , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND: Lipocalin-2 is an adipocytokine implicated in apoptosis, innate immunity, angiogenesis, and the development of chronic kidney disease. OBJECTIVES: To investigate the role of lipocalin-2 in systemic sclerosis (SSc). MATERIALS AND METHODS: Serum lipocalin-2 levels were determined by enzyme-linked immunosorbent assay in 50 patients with SSc and 19 healthy subjects. Lipocalin-2 expression was evaluated in the skin of patients with SSc and bleomycin (BLM)-treated mice and in Fli1-deficient endothelial cells by reverse transcriptase-real time polymerase chain reaction, immunoblotting and/or immunohistochemistry. RESULTS: Although serum lipocalin-2 levels were comparable between patients with SSc and healthy controls, the prevalence of scleroderma renal crisis was significantly higher in patients with SSc with elevated serum lipocalin-2 levels than in those with normal levels. Furthermore, serum lipocalin-2 levels inversely correlated with estimated glomerular filtration rate in patients with SSc with renal dysfunction. Among patients with SSc with normal renal function, serum lipocalin-2 levels positively correlated with skin score in patients with diffuse cutaneous SSc with disease duration of < 3 years and inversely correlated with estimated right ventricular systolic pressure in total patients with SSc. Importantly, in SSc lesional skin, lipocalin-2 expression was increased in dermal fibroblasts and endothelial cells. In BLM-treated mice, lipocalin-2 was highly expressed in dermal fibroblasts, but not in endothelial cells. On the other hand, the deficiency of transcription factor Fli1, which is implicated in SSc vasculopathy, induced lipocalin-2 expression in cultivated endothelial cells. CONCLUSIONS: Lipocalin-2 may be involved in renal dysfunction and dermal fibrosis of SSc. Dysregulated matrix metalloproteinase-9/lipocalin-2-dependent angiogenesis due to Fli1 deficiency may contribute to the development of pulmonary arterial hypertension associated with SSc.
Assuntos
Proteínas de Fase Aguda/fisiologia , Lipocalinas/fisiologia , Pneumopatias/etiologia , Proteínas Proto-Oncogênicas/fisiologia , Insuficiência Renal Crônica/etiologia , Escleroderma Sistêmico/etiologia , Pele/patologia , Doenças Vasculares/etiologia , Proteínas de Fase Aguda/metabolismo , Adulto , Idoso , Animais , Apoptose/fisiologia , Estudos de Casos e Controles , Feminino , Fibrose/etiologia , Fibrose/patologia , Fibrose/fisiopatologia , Taxa de Filtração Glomerular/fisiologia , Humanos , Lipocalina-2 , Lipocalinas/metabolismo , Pneumopatias/fisiopatologia , Masculino , Camundongos , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas/metabolismo , Escleroderma Sistêmico/patologia , Escleroderma Sistêmico/fisiopatologia , Dermatopatias Vasculares/etiologia , Dermatopatias Vasculares/fisiopatologia , Doenças Vasculares/patologia , Doenças Vasculares/fisiopatologiaRESUMO
Ciclosporin (Cs)A is an effective treatment for psoriasis. However, to date, the effect of CsA on the production of interleukins (ILs) is unknown. We investigated how CsA affects production of IL-12/23p40 and IL-23 production by the human monocyte cell line, THP-1, which is able to differentiate into macrophage-like cells or normal human keratinocytes (NHKs). THP-1 cells were preincubated with CsA, then stimulated with lipopolysaccharide (LPS), polyinosinic:polycytidylic acid or adenosine triphosphate. The levels of IL-12/23p40 and IL-23 released into the supernatant were assayed by ELISA. CsA significantly reduced both IL-12/23p40 and IL-23 production by LPS-stimulated THP-1 cells, but not in LPS-stimulated macrophage-like differentiated THP-1 cells. None of the stimuli used significantly induced either IL-12/23p40 or IL-23 production in NHKs. CsA inhibits not only IL-12/23p40 and IL-12p70, but also heterodimeric IL-23 production by human monocytes, which may be one possible mechanism for the therapeutic efficacy of CsA in psoriasis.
Assuntos
Ciclosporina/farmacologia , Inibidores Enzimáticos/farmacologia , Interleucina-12/metabolismo , Interleucina-23/metabolismo , Monócitos/efeitos dos fármacos , Linhagem Celular , Ensaio de Imunoadsorção Enzimática , Humanos , Monócitos/metabolismo , Psoríase/tratamento farmacológicoRESUMO
BACKGROUND: Patients with human immunodeficiency virus (HIV) infection exhibit various skin diseases. HIV-associated eosinophilic folliculitis (EF) and pruritic papular eruption (PPE) are frequently seen. OBJECTIVE: To understand the mechanisms underlying HIV-associated EF and PPE. METHODS: In order to know frequencies of EF and PPE among patients with HIV infection, we first collected HIV(+) patients who visited dermatology clinic in National Center for Global Health and Medicine during February 2007. We next collected 25 serum samples from HIV(+) patients with skin diseases from May 2008 to May 2010. Eight of 25 patients had EF (EF group), four had PPE (PPE group) and others had non-itchy skin problems such as condyloma acuminatum (no itch group). RESULTS: We first confirmed high frequencies of EF (10.7%) and PPE (5.3%) among 75 HIV(+) patients who visited our clinic during one month. We then measured serum levels of CCL11, CCL17, CCL26 and CCL27. Serum CCL17 levels in EF were significantly higher than those of PPE and no itch group. Serum CCL26 and CCL27 levels in EF were higher than those of no itch group. The number of CD4(+) cells in EF was significantly lower than that in no itch group. CONCLUSION: High serum levels of CCL17, CCL26 and CCL27, and low CD4(+) cell counts may account for the development of HIV-associated EF.
Assuntos
Quimiocinas/sangue , Eosinofilia/sangue , Foliculite/sangue , Infecções por HIV/complicações , Dermatopatias Vesiculobolhosas/sangue , Contagem de Linfócito CD4 , Ensaio de Imunoadsorção Enzimática , Eosinofilia/complicações , Foliculite/complicações , Humanos , Dermatopatias Vesiculobolhosas/complicaçõesRESUMO
BACKGROUND: CC chemokine ligand (CCL) 18 is expressed by monocytes and dendritic cells (DCs), and has potent chemotactic activity for T cells, B cells and DCs. CCL18 expression is up-regulated in lesional skin of atopic dermatitis and bullous pemphigoid, suggesting its important roles in the development of these skin diseases. OBJECTIVE: To investigate roles of CCL18 in cutaneous T-cell lymphoma (CTCL). METHODS: The CCL18 messenger RNA (mRNA) expression in CTCL skin (n = 21) and in normal skin (n = 7) was examined by quantitative RT-PCR. CCL18 expression was also examined by immunohistochemistry. Serum CCL18 levels were measured in 38 patients with CTCL and 20 healthy controls by enzyme-linked immunosorbent assay. We also analysed correlation between serum CCL18 levels and other clinical and laboratory data. RESULTS: The CTCL lesional skin contained higher levels of CCL18 mRNA than normal skin. CCL18 was expressed by dermal macrophages and DCs in CTCL skin. Serum CCL18 levels in patients with CTCL were significantly higher than those of healthy controls and correlated with types of skin lesions. They also significantly correlated with modified severity-weighted assessment scores, serum sIL-2R, LDH, IL-4, IL-10, IL-31, CCL17 and CCL26 levels. Patients with high serum levels of CCL18 showed significantly poor prognosis compared with those with low CCL18 levels. CONCLUSION: CCL18 mRNA is up-regulated in CTCL lesional skin, and serum CCL18 levels are significantly increased and correlated with the severity of CTCL. These results suggest that CCL18 may be associated with the development of CTCL.
Assuntos
Quimiocinas CC/genética , Regulação Neoplásica da Expressão Gênica , Linfoma Cutâneo de Células T/genética , Neoplasias Cutâneas/genética , Adulto , Idoso , Biópsia por Agulha , Estudos de Casos e Controles , Quimiocinas CC/metabolismo , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imuno-Histoquímica , Linfoma Cutâneo de Células T/patologia , Linfoma Cutâneo de Células T/fisiopatologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Prognóstico , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real/métodos , Valores de Referência , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/fisiopatologia , Estatísticas não Paramétricas , Regulação para CimaRESUMO
BACKGROUND: CD26 is a multifunctional type II transmembrane glycoprotein, which also exists as a secreted isoform, soluble CD26 (sCD26). The CD26 expression on circulating T cells is decreased in some skin diseases such as cutaneous T-cell lymphoma (CTCL) and psoriasis. It remains to be determined whether sCD26 can be used as a marker of skin diseases or not. OBJECTIVE: To investigate utility of sCD26 as a diagnostic marker of skin diseases in combination with thymus and activation-regulated chemokine (TARC). METHODS: Serum sCD26 levels were measured using enzyme-linked immunosorbent assay in 130 participants including 32 patients with atopic dermatitis (AD); 45 patients with CTCL; 26 patients with psoriasis; and 27 healthy controls. RESULTS: Serum sCD26 levels in patients with CTCL and psoriasis (162.1 ± 80.2 ng/mL and 125.4 ± 82.1 ng/mL respectively) were significantly lower than those of healthy controls (392.6 ± 198.7 ng/mL; P < 0.01 and 0.01 respectively). In patients with CTCL, serum sCD26 levels of patients with advanced stage were 135.0 ± 51.5 ng/mL and they were significantly lower than those with early stage (193.1 ± 96.0 ng/mL; P < 0.05). When we used serum sCD26 and TARC levels for diagnostic criteria, sensitivity, specificity, positive predictive value and negative predictive value for AD, CTCL and psoriasis were 65.2-73.7%, 81.4-97.6%, 65.2-94.4%, and 81.4-88.9% respectively. CONCLUSION: Serum sCD26 levels, combined with serum TARC levels, are helpful in diagnosis of AD, CTCL and psoriasis.
Assuntos
Quimiocina CCL17/sangue , Dermatite Atópica/sangue , Dipeptidil Peptidase 4/sangue , Linfoma Cutâneo de Células T/sangue , Psoríase/sangue , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Quimiocina CCL17/metabolismo , Dermatite Atópica/diagnóstico , Dermatite Atópica/fisiopatologia , Dipeptidil Peptidase 4/metabolismo , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Linfoma Cutâneo de Células T/diagnóstico , Linfoma Cutâneo de Células T/fisiopatologia , Masculino , Pessoa de Meia-Idade , Psoríase/diagnóstico , Psoríase/fisiopatologia , Valores de Referência , Medição de Risco , Sensibilidade e Especificidade , Índice de Gravidade de Doença , SolubilidadeRESUMO
BACKGROUND: Apelin is a bioactive peptide exerting its pro-angiogenic and pro-fibrotic effects in a context-dependent manner through the activation of its receptor APJ, which is ubiquitously expressed on the surface of various cell types. The activation of apelin/APJ signalling appears to be involved in the pathological process of fibrotic disorders, including liver cirrhosis. OBJECTIVE: As an initial step to clarify the role of apelin/APJ signalling in the pathogenesis of systemic sclerosis (SSc), we investigated serum apelin levels and their clinical association in patients with SSc. METHODS: Serum apelin levels were determined by a specific enzyme-linked immunosorbent assay in 56 SSc patients and 18 healthy controls. RESULTS: Serum apelin levels were comparable among three groups, including diffuse cutaneous SSc, limited cutaneous SSc and control subjects (1.77 ± 1.48, 1.63 ± 1.51 and 1.61 ± 0.44 ng/mL, respectively). When we classified SSc patients into three groups according to disease duration, serum apelin levels were elevated in early SSc (<3 years) compared with mid-stage SSc (3-10 years) (1.74 ± 1.26 vs. 1.02 ± 0.52 ng/mL, P < 0.05). Importantly, in late stage SSc (>10 years), the prevalence of severe vascular involvements, including intractable skin ulcers, scleroderma renal crisis and pulmonary arterial hypertension, was significantly higher in patients with elevated serum apelin levels than in those without (100% vs. 20%, P < 0.05). CONCLUSION: Apelin may be associated with altered and activated angiogenesis prior to fibrotic responses in early SSc and with the development of proliferative vasculopathy in late stage SSc.
Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/sangue , Neovascularização Patológica/sangue , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/fisiopatologia , Adulto , Idoso , Apelina , Biomarcadores/sangue , Estudos de Casos e Controles , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/fisiopatologia , Prognóstico , Valores de Referência , Medição de Risco , Esclerodermia Difusa/sangue , Esclerodermia Difusa/fisiopatologia , Esclerodermia Limitada/sangue , Esclerodermia Limitada/fisiopatologia , Sensibilidade e Especificidade , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Retinol binding protein-4 (RBP-4) is a member of adipocytokines, which is potentially associated with fibrosis, vasodilation, and angiogenesis in addition to insulin resistance. OBJECTIVE: To investigate the clinical significance of serum RBP4 levels in patients with systemic sclerosis (SSc), which is a systemic autoimmune disease characterized by fibrosis and vasculopathy. METHODS: Serum RBP4 levels were determined by enzyme-linked immunosorbent assay in 62 SSc patients and 19 healthy controls. RESULTS: Similar to patients with chronic kidney disease, serum RBP4 levels inversely correlated with estimated glomerular filtration rate in SSc patients with renal dysfunction. Therefore, analyses were carried out by excluding SSc patients with estimated glomerular filtration rate <60 mL/min/1.73 m(2) . Serum RBP4 levels were significantly lower in diffuse cutaneous SSc (dcSSc) than in control subjects [median (25-75 percentile); 25.8 µg/mL (19.6-47.0) vs. 43.1 µg/mL (31.7-53.4), P < 0.05], while there was no significant difference between limited cutaneous SSc (lcSSc) [28.0 µg/mL (25.4-43.3)] and control subjects. In both of dcSSc and lcSSc, patients with Raynaud's phenomenon had RBP4 levels significantly lower than those without. Furthermore, serum RBP4 levels inversely correlated with pulmonary function test results in dcSSc and with right ventricular systolic pressure in lcSSc. CONCLUSION Decreased RBP4 levels are associated with the prevalence of Raynaud's phenomenon in dcSSc and lcSSc, with the severity of interstitial lung disease in dcSSc, and with the degree of pulmonary vascular involvement in lcSSc, suggesting the possible contribution of RBP4 to the pathological events in this disorder.
Assuntos
Proteínas Plasmáticas de Ligação ao Retinol/metabolismo , Escleroderma Sistêmico/sangue , Ciclofosfamida/uso terapêutico , Ensaio de Imunoadsorção Enzimática , Feminino , Taxa de Filtração Glomerular , Humanos , Doenças Pulmonares Intersticiais/sangue , Masculino , Pessoa de Meia-Idade , Doença de Raynaud/sangue , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/fisiopatologiaRESUMO
BACKGROUND: A disintegrin and metalloprotease (ADAM) 12 is one of the metalloproteinase-type ADAMs and possesses extracellular metalloprotease and cell-binding functions. ADAM12 is expressed in two alternative forms, such as a membrane-anchored form (ADAM12-L) and a short secreted form (ADAM12-S). OBJECTIVE: To investigate the clinical significance of serum ADAM12-S levels in systemic sclerosis (SSc). METHODS: Serum ADAM12-S levels were determined by a specific enzyme-linked immunosorbent assay in 61 SSc patients and 18 healthy controls. RESULTS: Serum ADAM12-S levels were significantly increased in diffuse cutaneous SSc (dcSSc) patients than in healthy controls (0.417 ± 0.389 vs. 0.226 ± 0.065 ng/mL; P < 0.05), while being comparable between limited cutaneous SSc (0.282 ± 0.258 ng/mL) and healthy controls. Serum ADAM12-S levels significantly elevated in dcSSc patients with disease duration of ≤ 6 years (0.537 ± 0.449 ng/mL, P < 0.05), but not in dcSSc with disease duration of >6 years (0.225 ± 0.049 ng/mL), compared to healthy controls. Furthermore, in dcSSc patients with disease duration of ≤ 6 years, serum ADAM12-S levels correlated positively with modified Rodnan total skin thickness score, ground glass score, and serum C-reactive protein values, while showed inverse correlation with fibrosis score. CONCLUSION: Elevated serum ADAM12-S levels are associated with elevated serum inflammatory marker, severity of skin fibrosis, and activity of interstitial lung disease in dcSSc, suggesting the possible contribution of ADAM12-S to the pathological events in this disorder.
Assuntos
Proteínas ADAM/sangue , Doenças Pulmonares Intersticiais/sangue , Doenças Pulmonares Intersticiais/etiologia , Proteínas de Membrana/sangue , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/complicações , Proteína ADAM12 , Progressão da Doença , Feminino , Fibrose/sangue , Fibrose/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Pele/patologia , Fatores de TempoRESUMO
BACKGROUND: B-cell-activating factor belonging to the tumour necrosis factor family (BAFF) is known for its role in the survival and maturation of B cells. It has been recently suggested that BAFF also plays important roles in T-cell activation in T-cell mediated diseases such as psoriasis. OBJECTIVES: To investigate the role of BAFF in cutaneous T-cell lymphoma (CTCL). METHODS: BAFF messenger RNA (mRNA) expression in skin samples (24 CTCL cases and seven healthy controls) and in skin-derived fibroblasts (five CTCL cases and five healthy controls) was examined by quantitative reverse transcription-polymerase chain reaction. We also performed immunohistochemical staining for BAFF and its receptors. Serum BAFF levels were measured in patients with CTCL (n=46), atopic dermatitis (n=36) or psoriasis (n=27) and 27 healthy controls by enzyme-linked immunosorbent assay. RESULTS: Lesional skin of CTCL contained higher levels of BAFF mRNA than normal skin and the expression levels correlated with disease activity. BAFF mRNA expression levels were elevated in fibroblasts from CTCL skin. Tumour cells in the lesional skin of CTCL expressed BAFF and its receptors, while fibroblasts expressed only BAFF. Serum BAFF levels of CTCL patients were significantly higher than those of healthy controls and correlated with types of skin lesions and clinical stages. They also significantly correlated with serum soluble interleukin-2 receptor and lactate dehydrogenase levels. CONCLUSIONS: BAFF expression in CTCL skin and serum BAFF levels are significantly increased and correlate with the severity of CTCL. These results suggest that BAFF may have important roles in the development of CTCL.
Assuntos
Fator Ativador de Células B/metabolismo , Linfoma Cutâneo de Células T/metabolismo , Neoplasias Cutâneas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Progressão da Doença , Feminino , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismoRESUMO
BACKGROUND: The cell surface protein CD93, expressed on endothelial and myeloid cells, mediates phagocytosis, inflammation and cell adhesion. A soluble form of CD93 (sCD93) is released during inflammation. OBJECTIVES: To determine the serum sCD93 level and its association with clinical parameters in patients with systemic sclerosis (SSc). METHODS: Serum sCD93 levels were examined by enzyme-linked immunosorbent assay in 59 patients with SSc, 24 patients with systemic lupus erythematosus and 47 healthy individuals. The expression of CD93 in skin tissues was examined immunohistochemically. In a retrospective longitudinal study, sera from 11 patients with SSc were analysed. RESULTS: Serum sCD93 levels were increased in patients with SSc compared with healthy individuals (P<0·001). Patients with diffuse cutaneous SSc showed greater levels of sCD93 than those with limited cutaneous SSc (P<0·01) or systemic lupus erythematosus (P<0·01). Serum sCD93 levels correlated positively with the severity of skin sclerosis. Strong CD93 immunostaining was observed on endothelial cells in lesional skin tissues. In the longitudinal study, sCD93 levels decreased in parallel with improvement in skin sclerosis. CONCLUSIONS: Serum sCD93 levels are increased in patients with SSc and correlate with the severity and activity of skin sclerosis. CD93 may contribute to the development of skin fibrosis in SSc.
Assuntos
Glicoproteínas de Membrana/metabolismo , Receptores de Complemento/metabolismo , Escleroderma Sistêmico/sangue , Adolescente , Adulto , Idoso , Criança , Feminino , Humanos , Imuno-Histoquímica , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Pele/metabolismo , Adulto JovemRESUMO
BACKGROUND: A noncanonical pathway of transforming growth factor-ß signalling, the c-Abl/protein kinase C-δ (PKC-δ)/Friend leukemia virus integration 1 (Fli1) axis, is a powerful regulator of collagen synthesis in dermal fibroblasts. OBJECTIVES: To investigate the significance of the c-Abl/PKC-δ/Fli1 pathway for the establishment of the profibrotic phenotype in lesional dermal fibroblasts from patients with localized scleroderma (LSc). METHODS: The activation status of the c-Abl/PKC-δ/Fli1 pathway was evaluated by immunoblotting and chromatin immunoprecipitation using cultured dermal fibroblasts from patients with LSc and closely matched healthy controls and by immunostaining on skin sections. The effects of a platelet-derived growth factor receptor inhibitor AG1296 and gene silencing of c-Abl on the expression levels of type I collagen were evaluated by immunoblotting. RESULTS: The phosphorylation levels of Fli1 at threonine 312 were increased, while the total Fli1 levels and the binding of Fli1 to the COL1A2 promoter were decreased, in cultured LSc fibroblasts compared with cultured normal fibroblasts. Furthermore, in cultured LSc fibroblasts, the expression levels of c-Abl were elevated compared with cultured normal fibroblasts and PKC-δ was preferentially localized in the nucleus. These findings were also confirmed in vivo by immunohistochemistry using skin sections. Moreover, gene silencing of c-Abl, but not AG1296, significantly suppressed the expression of type I collagen in cultured LSc fibroblasts. CONCLUSIONS: Constitutive activation of the c-Abl/PKC-δ/Fli1 pathway at least partially contributes to the establishment of the profibrotic phenotype in LSc dermal fibroblasts, which provides a novel molecular basis to explain the efficacy of imatinib against skin sclerosis in a certain subset of LSc.
Assuntos
Fibroblastos/metabolismo , Proteína Quinase C-delta/metabolismo , Proteína Proto-Oncogênica c-fli-1/metabolismo , Proteínas Proto-Oncogênicas c-abl/metabolismo , Esclerodermia Localizada/metabolismo , Adolescente , Adulto , Benzamidas , Estudos de Casos e Controles , Células Cultivadas , Criança , Pré-Escolar , Feminino , Fibroblastos/efeitos dos fármacos , Humanos , Mesilato de Imatinib , Masculino , Pessoa de Meia-Idade , Fosforilação , Piperazinas/farmacologia , Proteína Quinase C-delta/genética , Inibidores de Proteínas Quinases/farmacologia , Proteína Proto-Oncogênica c-fli-1/genética , Pirimidinas/farmacologia , Esclerodermia Localizada/genética , Fator de Crescimento Transformador beta/efeitos dos fármacos , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismoRESUMO
The protein lipocalin (LCN)-2 is known to be related to insulin resistance, obesity and atherosclerotic diseases. Psoriasis is an inflammatory skin disease related to metabolic syndrome. The aim of this study was to examine the relationship between serum LCN2 levels and indicators for metabolic syndrome and inflammatory cytokine levels in patients with psoriasis. Serum LCN2 levels were measured in patients with psoriasis, atopic dermatitis (AD) or bullous pemphigoid (BP), and compared with those of healthy controls. Serum LCN2 levels were also compared with several indicators for metabolic syndrome, and with serum levels of interleukin (IL)-6 and tumour necrosis factor (TNF)-α, two markers of inflammation. Serum LCN2 levels in patients with psoriasis were significantly higher than those of healthy controls, but there was no significant correlation between serum LCN2 and body mass index. Serum LCN2 levels also correlated with serum IL-6 and TNF-α levels in patients with psoriasis. Serum LCN2 levels are a general indicator for increased inflammation in the patients with psoriasis.