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4.
Br J Dermatol ; 178(6): 1373-1382, 2018 06.
Article in English | MEDLINE | ID: mdl-29238954

ABSTRACT

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.


Subject(s)
Interleukin-17/physiology , Lymphoma, T-Cell, Cutaneous/immunology , Th2 Cells/immunology , Tumor Microenvironment/immunology , Cell Line , Disease Progression , Female , Humans , Interleukin-13/biosynthesis , Interleukin-17/metabolism , Keratinocytes/immunology , Leukocytes, Mononuclear/metabolism , Male , Middle Aged , Phosphorylation/immunology , Receptors, Interleukin/immunology , STAT6 Transcription Factor/metabolism , Up-Regulation/immunology
5.
Ann Oncol ; 28(10): 2517-2525, 2017 Oct 01.
Article in English | MEDLINE | ID: mdl-28961843

ABSTRACT

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.


Subject(s)
Mycosis Fungoides/therapy , Sezary Syndrome/therapy , Adolescent , Adult , Aged , Aged, 80 and over , Australia/epidemiology , Brazil/epidemiology , Child , Europe/epidemiology , Female , Humans , Japan/epidemiology , Male , Medical Oncology/methods , Medical Oncology/statistics & numerical data , Middle Aged , Mycosis Fungoides/mortality , Mycosis Fungoides/pathology , Neoplasm Staging , Retrospective Studies , Sezary Syndrome/mortality , Sezary Syndrome/pathology , United States/epidemiology , Young Adult
7.
Br J Dermatol ; 175(6): 1195-1203, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27105895

ABSTRACT

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.


Subject(s)
Cathelicidins/physiology , Scleroderma, Systemic/etiology , Skin/pathology , Vascular Diseases/etiology , Adult , Aged , Animals , Antimicrobial Cationic Peptides/metabolism , Cathelicidins/metabolism , Endothelial Cells/metabolism , Female , Fibrosis/blood , Fibrosis/etiology , Humans , Interferon-alpha/metabolism , Mice, Inbred C57BL , Middle Aged , Proto-Oncogene Protein c-fli-1/deficiency , Scleroderma, Systemic/blood , Up-Regulation/physiology , Vascular Diseases/blood
8.
Oncogene ; 35(28): 3692-704, 2016 07 14.
Article in English | MEDLINE | ID: mdl-26640145

ABSTRACT

Multiple sequential genetic and epigenetic alterations underlie cancer development and progression. Overcoming cellular senescence is an early step in cancer pathogenesis. Here, we demonstrate that a noncoding regulatory RNA, microRNA-16 (miR-16), has the potential to induce cellular senescence. First, we examined the expression of miR-16 in primary cutaneous T-cell lymphoma (CTCL) and other non-Hodgkin T/natural killer (NK)-cell lymphomas and found that miR-16 was downregulated than that in the corresponding normal cells. Notably, miR-16 expression was reduced as the primary CTCL progressed from the early stage to the advanced stage. Next, we transduced CTCL cells with miR-16 to examine whether this miRNA exhibited tumor-suppressive effects in CTCL cells. In CTCL cells expressing wild-type p53, forced expression of miR-16 enhanced p21 expression via downregulation of the polycomb group protein Bmi1, thereby inducing cellular senescence. Alternatively, in CTCL cells lacking functional p53, miR-16 induced compensatory apoptosis. The miR-16 transfection significantly decreased senescent cells and increased apoptotic cells in p21-knockdown CTCL cells expressing wild-type p53, suggesting that the presence or absence of p21 may be the most important condition in the senescence-apoptosis switch in CTCL lymphomagenesis. Furthermore, we found that the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) restored the expression of miR-16 and its essential targets, induced senescence in CTCL cells expressing wild-type p53 and promoted apoptosis in cells with nonfunctional p53. Moreover, we found that other T/NK-cell lymphoma cell lines showed similar tumor-suppressive effects in response to miR-16 and SAHA and that these effects were dependent on p53 status. These results suggested that epigenetic silencing of miR-16 may be a key step during lymphoma development. Elucidation of the essential targets of miR-16 and SAHA provides a basis for the clinical application of SAHA in the treatment of CTCL and other non-Hodgkin T/NK-cell lymphomas.


Subject(s)
Apoptosis/genetics , Cellular Senescence/genetics , Gene Expression Regulation, Neoplastic/genetics , Lymphoma, Non-Hodgkin/genetics , Lymphoma, T-Cell, Cutaneous/genetics , MicroRNAs/genetics , Animals , Blotting, Western , Cell Line, Tumor , Cyclin-Dependent Kinase Inhibitor p21/genetics , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Female , Gene Expression Regulation, Neoplastic/drug effects , Histone Deacetylase Inhibitors/pharmacology , Humans , Hydroxamic Acids/pharmacology , Lymphoma, Non-Hodgkin/metabolism , Lymphoma, Non-Hodgkin/pathology , Lymphoma, T-Cell, Cutaneous/metabolism , Lymphoma, T-Cell, Cutaneous/pathology , Mice, Inbred NOD , Mice, Knockout , Mice, SCID , Polycomb Repressive Complex 1/genetics , Polycomb Repressive Complex 1/metabolism , RNA Interference , Reverse Transcriptase Polymerase Chain Reaction , Transplantation, Heterologous , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Vorinostat
9.
Clin Exp Dermatol ; 41(2): 183-9, 2016 Mar.
Article in English | MEDLINE | ID: mdl-25976154

ABSTRACT

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.


Subject(s)
Interleukin-33/metabolism , Psoriasis/metabolism , Adult , Analysis of Variance , C-Reactive Protein/metabolism , Case-Control Studies , Cytokines/metabolism , Female , Humans , Interleukins/metabolism , Keratinocytes/metabolism , Male , Middle Aged , Psoriasis/blood , Tumor Necrosis Factor-alpha/metabolism , Vascular Endothelial Growth Factor A/metabolism
10.
Br J Dermatol ; 174(2): 338-47, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26399195

ABSTRACT

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.


Subject(s)
Antigens, CD/physiology , Proto-Oncogene Protein c-fli-1/deficiency , Receptors, Cell Surface/physiology , Scleroderma, Systemic/etiology , Adult , Aged , Analysis of Variance , Animals , Bleomycin/pharmacology , Bosentan , Case-Control Studies , Cells, Cultured , Down-Regulation/physiology , Endothelial Cells/metabolism , Endothelial Protein C Receptor , Endothelin Receptor Antagonists/pharmacology , Endothelium, Vascular/metabolism , Enzyme-Linked Immunosorbent Assay , Female , Fibrinolysin/drug effects , Humans , Male , Mice , Microvessels/metabolism , Middle Aged , Scleroderma, Systemic/blood , Sulfonamides/pharmacology , Thrombophilia/etiology , alpha-2-Antiplasmin/drug effects
11.
Br J Dermatol ; 173(3): 681-9, 2015 Sep.
Article in English | MEDLINE | ID: mdl-25781362

ABSTRACT

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.


Subject(s)
Acute-Phase Proteins/physiology , Lipocalins/physiology , Lung Diseases/etiology , Proto-Oncogene Proteins/physiology , Renal Insufficiency, Chronic/etiology , Scleroderma, Systemic/etiology , Skin/pathology , Vascular Diseases/etiology , Acute-Phase Proteins/metabolism , Adult , Aged , Animals , Apoptosis/physiology , Case-Control Studies , Female , Fibrosis/etiology , Fibrosis/pathology , Fibrosis/physiopathology , Glomerular Filtration Rate/physiology , Humans , Lipocalin-2 , Lipocalins/metabolism , Lung Diseases/physiopathology , Male , Mice , Middle Aged , Proto-Oncogene Proteins/metabolism , Scleroderma, Systemic/pathology , Scleroderma, Systemic/physiopathology , Skin Diseases, Vascular/etiology , Skin Diseases, Vascular/physiopathology , Vascular Diseases/pathology , Vascular Diseases/physiopathology
15.
Clin Exp Dermatol ; 38(5): 545-8, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23777496

ABSTRACT

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.


Subject(s)
Cyclosporine/pharmacology , Enzyme Inhibitors/pharmacology , Interleukin-12/metabolism , Interleukin-23/metabolism , Monocytes/drug effects , Cell Line , Enzyme-Linked Immunosorbent Assay , Humans , Monocytes/metabolism , Psoriasis/drug therapy
16.
J Eur Acad Dermatol Venereol ; 27(2): e212-6, 2013 Feb.
Article in English | MEDLINE | ID: mdl-22672135

ABSTRACT

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.


Subject(s)
Chemokines/blood , Eosinophilia/blood , Folliculitis/blood , HIV Infections/complications , Skin Diseases, Vesiculobullous/blood , CD4 Lymphocyte Count , Enzyme-Linked Immunosorbent Assay , Eosinophilia/complications , Folliculitis/complications , Humans , Skin Diseases, Vesiculobullous/complications
17.
J Eur Acad Dermatol Venereol ; 27(1): e60-7, 2013 Jan.
Article in English | MEDLINE | ID: mdl-22404649

ABSTRACT

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.


Subject(s)
Chemokines, CC/genetics , Gene Expression Regulation, Neoplastic , Lymphoma, T-Cell, Cutaneous/genetics , Skin Neoplasms/genetics , Adult , Aged , Biopsy, Needle , Case-Control Studies , Chemokines, CC/metabolism , Disease Progression , Enzyme-Linked Immunosorbent Assay , Female , Humans , Immunohistochemistry , Lymphoma, T-Cell, Cutaneous/pathology , Lymphoma, T-Cell, Cutaneous/physiopathology , Male , Middle Aged , Neoplasm Invasiveness/pathology , Prognosis , RNA, Messenger/metabolism , Real-Time Polymerase Chain Reaction/methods , Reference Values , Skin Neoplasms/pathology , Skin Neoplasms/physiopathology , Statistics, Nonparametric , Up-Regulation
18.
J Eur Acad Dermatol Venereol ; 27(3): 337-44, 2013 Mar.
Article in English | MEDLINE | ID: mdl-22211766

ABSTRACT

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.


Subject(s)
Retinol-Binding Proteins, Plasma/metabolism , Scleroderma, Systemic/blood , Cyclophosphamide/therapeutic use , Enzyme-Linked Immunosorbent Assay , Female , Glomerular Filtration Rate , Humans , Lung Diseases, Interstitial/blood , Male , Middle Aged , Raynaud Disease/blood , Scleroderma, Systemic/drug therapy , Scleroderma, Systemic/physiopathology
19.
J Eur Acad Dermatol Venereol ; 27(1): 19-24, 2013 Jan.
Article in English | MEDLINE | ID: mdl-22077186

ABSTRACT

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.


Subject(s)
Chemokine CCL17/blood , Dermatitis, Atopic/blood , Dipeptidyl Peptidase 4/blood , Lymphoma, T-Cell, Cutaneous/blood , Psoriasis/blood , Adult , Biomarkers/blood , Case-Control Studies , Chemokine CCL17/metabolism , Dermatitis, Atopic/diagnosis , Dermatitis, Atopic/physiopathology , Dipeptidyl Peptidase 4/metabolism , Disease Progression , Enzyme-Linked Immunosorbent Assay , Female , Humans , Lymphoma, T-Cell, Cutaneous/diagnosis , Lymphoma, T-Cell, Cutaneous/physiopathology , Male , Middle Aged , Psoriasis/diagnosis , Psoriasis/physiopathology , Reference Values , Risk Assessment , Sensitivity and Specificity , Severity of Illness Index , Solubility
20.
J Eur Acad Dermatol Venereol ; 27(1): 37-42, 2013 Jan.
Article in English | MEDLINE | ID: mdl-22112232

ABSTRACT

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.


Subject(s)
Intercellular Signaling Peptides and Proteins/blood , Neovascularization, Pathologic/blood , Scleroderma, Systemic/blood , Scleroderma, Systemic/physiopathology , Adult , Aged , Apelin , Biomarkers/blood , Case-Control Studies , Disease Progression , Enzyme-Linked Immunosorbent Assay , Female , Humans , Intercellular Signaling Peptides and Proteins/metabolism , Male , Middle Aged , Neovascularization, Pathologic/physiopathology , Prognosis , Reference Values , Risk Assessment , Scleroderma, Diffuse/blood , Scleroderma, Diffuse/physiopathology , Scleroderma, Limited/blood , Scleroderma, Limited/physiopathology , Sensitivity and Specificity , Severity of Illness Index
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