Risk of developing psoriasis in patients with schizophrenia: a nationwide retrospective cohort study.

BACKGROUND: Schizophrenia is a complex disease which proceeds from an interaction between genetic background and environmental factors. Recent studies showed T helper 17 (Th17) signalling, which is the main downstream immune response of psoriasis, is activated in schizophrenia. OBJECTIVE: To investigate whether patients with schizophrenia have higher risk of psoriasis. METHODS: In this nationwide retrospective cohort study, we analysed the 1 million enrollees' cohort from Taiwan's National Health Insurance Research Database. Psoriasis and schizophrenia were ascertained by International Classification of Diseases, 9th revision, Clinical Modification coding. The study cohort was comprised of enrollees diagnosed with schizophrenia during the period from 1 January 1996 through 31 December 2010, while the comparison population consisted of enrollees who had not been diagnosed with schizophrenia during the study period. Hazard ratio (HR) and 95% confidence interval (CI) were calculated for the risk of psoriasis associated with schizophrenia using Cox proportional hazard regression. RESULTS: The adjusted HR of psoriasis associated with schizophrenia was 2.32 (95% CI = 1.81-2.98). After 15 years, the cumulative incidence of psoriasis in patients with schizophrenia and comparison population was 2.82% and 1.17%, respectively. The Kaplan-Meier curves for the cumulative incidence of psoriasis in individuals with and without schizophrenia differed significantly (P < 0.0001, log-rank test). CONCLUSIONS: Patients with schizophrenia have higher risk of psoriasis, which may be due to common genetic susceptibilities and/or immunologic mechanisms in both diseases. Th17 signalling and pro-inflammatory cytokines may act as a link between these two diseases and are potential therapeutic targets for schizophrenia.

Tacrolimus abrogates TGF-ß1-induced type I collagen production in normal human fibroblasts through suppressing p38MAPK signalling pathway: implications on treatment of chronic atopic dermatitis lesions.

BACKGROUND: Atopic dermatitis (AD) is a commonly encountered inflammatory skin disease. Although acute lesions of acute AD are characterized by intense inflammation, the hallmarks of chronic AD lesions include lichenified fibrosis and thickening of the upper dermis. The increased expression of transforming growth factor beta 1 (TGF-ß1), a well-known fibrogenic cytokine, is observed in chronic AD lesions. Tacrolimus (FK506) ointment has been reported to be effective for treating AD as well as some TGF-ß1-induced fibrotic diseases. OBJECTIVES: To evaluate the effect of tacrolimus on TGF-ß1-stimulated cultured normal human dermal fibroblasts and explore the potential signalling pathways involved. METHODS: Fibroblasts cultured from healthy adult human foreskins were treated with TGF-ß1 with or without tacrolimus. The impact on cell viability and proliferation were assessed by [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) assay and BrdU incorporation assay respectively. Reverse transcription-polymerase chain reaction (RT-PCR), quantitative real-time PCR, enzyme-linked immunosorbent assay (ELISA) and western blotting were performed to evaluate the relevant expressions of mRNA or proteins in fibroblasts. RESULTS: Our results revealed that the increased expressions of transforming growth factor-ß receptor I (TGF-ßRI) and TGF-ßRII in TGF-ß1-treated fibroblasts were suppressed by tacrolimus treatment. In addition, tacrolimus significantly inhibited fibroblast proliferation enhanced by TGF-ß1. TGF-ß1 increased type I collagen production, and this enhancing effect was suppressed by tacrolimus. The down-regulation of MMP-1 and up-regulation of TIMP-1 induced by TGF-ß1 were reversed by tacrolimus. The increase in phosphorylated p38 mitogen-activated protein kinase (p38MAPK) expression stimulated by TGF-ß1 was down-regulated by tacrolimus. Moreover, the fibroblasts treated with p38MAPK inhibitor significantly reduced type I collagen expression induced by TGF-ß1. CONCLUSIONS: The present results demonstrated that tacrolimus significantly inhibited physiological functions of fibroblasts enhanced by TGF-ß1 in vitro. Clinically, we propose that topical tacrolimus may not only reduce AD recurrence but also ameliorate dermal fibrosis often seen in chronic AD lesions.

Psoriasis as initiator or amplifier of the systemic inflammatory march: impact on development of severe vascular events and implications for treatment strategy.

BACKGROUND: Psoriasis is a systemic disease associated with metabolic disorders and vascular complications. Both psoriasis and metabolic disorders are associated with systemic inflammation. We hypothesized that the sequence of events between the onset of psoriasis and metabolic disorder may affect the risk for subsequent development of vascular complications. METHODS: Nested case-control study was performed using the Taiwan National Health Insurance database. Accordingly, a total of 8180 psoriatic patients and 163,600 controls were included. Psoriasis was considered as the initiator of inflammatory march if metabolic disorder, including hypertension, diabetes mellitus and dyslipidemia, developed after onset of psoriasis. In patients with pre-existing metabolic disorder, psoriasis was considered as the amplifier of inflammatory march. RESULTS: In patients whose psoriasis served as the disease initiator, a lower risk for developing vascular disease (HR = 1.49; 95% CI = 1.11-2.00 and HR = 1.64; 95% CI = 1.31-2.05 for cerebrovascular and cardiovascular events, respectively) was found compared with patients whose psoriasis served as the disease amplifier (HR = 2.26; 95% CI = 1.72-2.97 and HR = 2.78; 95% CI = 2.26-3.42 for cerebrovascular and cardiovascular events, respectively) after adjusting for age and gender. In terms of treatment implications, methotrexate was associated with reduced risk for developing cerebrovascular event (HR = 0.22; 95% CI = 0.05-0.88) only in patients with psoriasis serving as the disease amplifier. CONCLUSIONS: Our results suggested that two scenarios of systemic inflammatory marches are present among psoriatic patients with metabolic disorder and judicious use of methotrexate may reduce the risk of cerebrovascular event, especially when psoriasis served as the disease amplifier of the systemic inflammatory march.

FK506 inhibits the enhancing effects of transforming growth factor (TGF)-ß1 on collagen expression and TGF-ß/Smad signalling in keloid fibroblasts: implication for new therapeutic approach.

BACKGROUND: Keloid is a unique proliferative disorder of fibroblasts resulting from derailment of the typical wound healing process. Due to lack of animal models for therapeutic testing, treatment of keloids remains a clinical challenge. Transforming growth factor (TGF)-ß1-related signalling plays a key role in keloid formation. As tacrolimus (FK506) has been reported to inhibit the effects of TGF-ß1 on cultured fibroblasts, we hypothesized that FK506 may be useful in treating keloids. OBJECTIVES: To explore the effects of FK506 on TGF-ß1-stimulated keloid fibroblasts (KFs) in terms of proliferation, migration and collagen production and to investigate the regulatory pathways involved. METHODS: Fibroblasts derived from keloids were treated with TGF-ß1 with or without FK506. Relevant assays including 5-bromo-2'-deoxyuridine incorporation assay, in vitro scratch assay, reverse transcription-polymerase chain reaction (PCR), quantitative PCR and Western blotting were performed. RESULTS: The proliferation and migration of KFs were significantly higher than those of normal fibroblasts. FK506 markedly inhibited KF proliferation, migration and collagen production enhanced by TGF-ß1. The increase in TGF-ß receptor I and II expression in TGF-ß1-treated KFs was suppressed by FK506 treatment. TGF-ß1 increased the phosphorylation of Smad2/3 and Smad4 in KFs, and this enhancing effect was abrogated by FK506. In addition, FK506 significantly increased the expression of Smad7 which was suppressed by TGF-ß1 treatment. CONCLUSIONS: Our results demonstrate that FK506 effectively blocks the TGF-ß/Smad signalling pathway in KFs by downregulation of TGF-ß receptors and suggest that FK506 may be included in the armamentarium for treating keloids.

Revised classification/nomenclature of vitiligo and related issues: the Vitiligo Global Issues Consensus Conference.

During the 2011 International Pigment Cell Conference (IPCC), the Vitiligo European Taskforce (VETF) convened a consensus conference on issues of global importance for vitiligo clinical research. As suggested by an international panel of experts, the conference focused on four topics: classification and nomenclature; definition of stable disease; definition of Koebner's phenomenon (KP); and 'autoimmune vitiligo'. These topics were discussed in seven working groups representing different geographical regions. A consensus emerged that segmental vitiligo be classified separately from all other forms of vitiligo and that the term 'vitiligo' be used as an umbrella term for all non-segmental forms of vitiligo, including 'mixed vitiligo' in which segmental and non-segmental vitiligo are combined and which is considered a subgroup of vitiligo. Further, the conference recommends that disease stability be best assessed based on the stability of individual lesions rather than the overall stability of the disease as the latter is difficult to define precisely and reliably. The conference also endorsed the classification of KP for vitiligo as proposed by the VETF (history based, clinical observation based, or experimentally induced). Lastly, the conference agreed that 'autoimmune vitiligo' should not be used as a separate classification as published evidence indicates that the pathophysiology of all forms of vitiligo likely involves autoimmune or inflammatory mechanisms.

High-glucose environment reduces human ß-defensin-2 expression in human keratinocytes: implications for poor diabetic wound healing.

BACKGROUND: Wound healing is a dynamic and complicated process in which inflammation, re-epithelialization and angiogenesis play important roles. Intriguingly, all three processes have been found to be defective during diabetic wound healing conditions. One common denominator associated with regulation of these events is human ß-defensin-2 (hBD2). It has been shown that skin wounding induces cutaneous hBD2 expression, and diabetic wounds have been associated with inadequate hBD expression. OBJECTIVES: The current study was launched to explore the effects of a high-glucose environment on cultured human keratinocytes. METHODS: Human keratinocytes were exposed to indicated culture conditions. The mRNA and protein levels of hBD2 were determined, and activation of relevant pathways was evaluated. The small interference RNA approach was used to validate the functional role of the proposed pathway on hBD2 expression. RESULTS: We showed that high-glucose cultivated keratinocytes expressed reduced levels of hBD2 and phosphorylated signal transducer and activator of transcription (pSTAT)-1 constitutively. In addition, pSTAT-1 signalling is critically involved in hBD2 expression. Formation of advanced glycation endproducts, a direct consequence of a high-glucose environment, involves constitutive downregulation of pSTAT-1 and hBD2. The addition of interleukin-1ß, an important cytokine during the cutaneous wound healing process, enabled the upregulation of hBD2 expression of both normal- and high-glucose cultivated keratinocytes, but the absolute levels of hBD2 were still significantly lower in the high-glucose-treated group. CONCLUSIONS: As hBD2 plays multifaceted roles during the wound healing process, the inadequate expression of hBD2 during diabetic conditions contributes to impaired wound healing.

Narrow-band UVB irradiation stimulates the migration and functional development of vitiligo-IgG antibodies-treated pigment cells.

BACKGROUND: The pathogenesis of vitiligo remains unclear. Most authorities favoured the autoimmune cause for the strong associations of vitiligo with multiple autoimmune diseases and the presence of autoantibodies in vitiligo patients. Narrow-band UVB (NBUVB) irradiation has been considered to be an effective treatment for vitiligo with simple treatment procedure and decreased accumulated ultraviolet exposure doses. OBJECTIVES: The aim this study was to investigate the effects of NBUVB irradiation on normal IgG antibodies (N-IgG) or vitiligo IgG antibodies (V-IgG)-treated NCCmelan5 cells in terms of proliferation, migration and melanin formation. METHODS: Cultured NCCmelan5 cells were treated with (i) NBUVB irradiation alone, (ii) N-IgG or V-IgG alone, and (iii) combination of N-IgG or V-IgG with NBUVB irradiation. The proliferation of NCCmelan5 cells were evaluated using BrdU incorporation assay. Western blotting was used to determine the expressions of phosphorylated p125(FAK) (pp125(FAK)) and tyrosinase in NCCmelan5 cells. The locomotion of NCCmelan5 cells was assessed using time-lapse assay and in vitro wound scratch assay. RESULTS: Neither N-IgG nor V-IgG significantly affected the proliferation of NCCmelan5 cells. The migration, melanin formation and tyrosinase expression in NCCmelan5 cells were decreased by V-IgG. NBUVB irradiation increased the proliferation of V-IgG treated NCCmelan5 cells. In addition, NBUVB irradiation enhanced the mobility of V-IgG-treated NCCmelan5 cells via upregulation of pp125(FAK). The melanogenesis and tyrosinase expression in V-IgG-treated NCCmelan5 cells were promoted using NBUVB irradiation. CONCLUSIONS: Our study demonstrated that the deleterious effects of V-IgG in the pathogenesis of vitiligo might be overcome by NBUVB irradiation.

Noninvasive cutaneous blood flow as a response predictor for visible light therapy on segmental vitiligo: a prospective pilot study.

BACKGROUND: Visible light is a treatment option for segmental vitiligo (SV), and visible light-induced repigmentation is associated with normalization of sympathetic dysfunction. Currently, it is difficult to predict individual patients' response to visible light therapy. OBJECTIVES: To test whether cutaneous blood flow can serve as a response predictor for visible light on treating SV. METHODS: Fourteen patients with SV were recruited in this prospective pilot study. Laser Doppler flowmetry was used to evaluate the cutaneous blood flow over SV lesions and contralateral normal skin. The pretreatment blood flow evaluation consisted of two stages: stage 1, following cold stress without prior visible light irradiation, and stage 2, following cold stress with prior visible light irradiation. Subsequently, the patients received regular visible light treatment for 3months, and a comparison of the pretreatment blood flow patterns between the visible light responding and nonresponding groups was carried out at the end of the study period. RESULTS: The SV lesions showed different blood flow profiles as compared with the contralateral normal skin. At the end of the 3-month study period, seven (50%) patients showed clinical repigmentation of >25%. The visible light responding group showed a more consistent occurrence of increased blood flow after stage 2 of the pretreatment evaluation while the nonresponding counterpart showed no significant changes. CONCLUSIONS: Normalization of sympathetic dysfunction may account for the efficacy of visible light in treating SV. Evaluation of cutaneous blood flow with and without prior visible light irradiation on cold-stressed SV lesions may serve as a treatment response predictor.

FK506 (tacrolimus) and endothelin combined treatment induces mobility of melanoblasts: new insights into follicular vitiligo repigmentation induced by topical tacrolimus on sun-exposed skin.

BACKGROUND: Topical tacrolimus (FK506) has been considered as a treatment option for treating vitiligo, a dermatosis characterized by disappearance of melanocytes (MCs). Previous reports have shown that a significant portion of treated patients demonstrated follicular repigmentation, indicating that the activation of MC precursor cells residing in the outer root sheath of hair follicles played an important role during the tacrolimus-induced repigmentation process. OBJECTIVES: To investigate the mechanisms involved in follicular pigmentation induced by topical tacrolimus. METHODS: As stem cells of MC lineage are identified in the lower portion of mouse hair follicles throughout the hair cycle, immature mouse melanoblasts (MBs) derived from neural crest cells (NCCmelb4) were used for this study. Relevant maturation parameters were evaluated. RESULTS: Our results revealed that FK506 stimulated the expressions of protein kinase A, protein kinase C and phosphorylated p38 mitogen-activated protein kinase. However, cell motility, a parameter associated with MB differentiation, was not enhanced by FK506 treatment. Endothelin (ET)-3, a prodifferentiation factor of MBs, also failed to promote NCCmelb4 cell locomotion. Combining ET-3 and FK506, however, stimulated cell mobility. ET B receptor, which was not present in NCCmelb4 cells, was induced after FK506 treatment. CONCLUSIONS: In summary, we have shown that FK506 is an efficient differentiation-stimulating agent, especially for cells of neural origin. The clinical efficacy of topical tacrolimus on vitiligo may be enhanced by combination with ET-3.

Topical tacrolimus has a limited direct effect on ultraviolet B-irradiated keratinocytes: implications for its photocarcinogenic potential.

BACKGROUND: Topical tacrolimus has shown remarkable clinical efficacy in treating many dermatoses. Combining ultraviolet (UV) B and tacrolimus is an intriguing therapeutic regimen, especially for treatment of vitiligo, for which combination therapy may show greater clinical efficacy than topical tacrolimus alone. The photocarcinogenic potential of such a regimen is unclear, and conflicting results have been reported by different investigators. AIM: To clarify this important clinical issue, we investigated the effects of tacrolimus on UVB-irradiated cultured keratinocytes in terms of apoptosis, differentiation, cell-cycle regulation and DNA damage. METHODS: Cultured keratinocytes were treated with tacrolimus before and after UVB irradiation and the various cellular physiological changes were evaluated using trypan blue exclusion, terminal dUTP nick-end labelling, flow cytometry and Western blotting analyses. RESULTS: Our results showed that treatment of tacrolimus before or after UVB irradiation had no significant effects on cultured keratinocytes in terms of cell apoptosis, transglutaminase-1, involucrin expression, cell-cycle progression and phospho-H(2)AX compared with UVB irradiation alone. CONCLUSION: The direct effect of tacrolimus on UVB-irradiated keratinocytes is small, suggesting that clinical regimens combining UVB and tacrolimus also have a limited direct effect on healthy skin compared with UVB irradiation alone.

Low-energy helium-neon laser induces melanocyte proliferation via interaction with type IV collagen: visible light as a therapeutic option for vitiligo.

BACKGROUND: The treatment of vitiligo remains a challenge for clinical dermatologists. We have previously shown that the helium-neon laser (He-Ne laser, 632.8 nm) is a therapeutic option for treatment of this depigmentary disorder. OBJECTIVES: Addressing the intricate interactions between melanocytes, the most important cellular component in the repigmentation scheme of vitiligo, and their innate extracellular matrix collagen type IV, the current study aimed to elucidate the effects of the He-Ne laser on melanocytes. METHODS: Cultured melanocytes were irradiated with the He-Ne laser. Relevant biological parameters including cell attachment, locomotion and growth were evaluated. In addition, the potentially involved molecular pathways were also determined. RESULTS: Our results show that in addition to suppressing mobility but increasing attachment to type IV collagen, the He-Ne laser stimulates melanocyte proliferation through enhanced alpha2beta1 integrin expression. The expression of phosphorylated cyclic-AMP response element binding protein (CREB), an important regulator of melanocyte growth, was also upregulated by He-Ne laser treatment. Using a specific mitochondrial uncoupling agent [carbonyl cyanide m-chlorophenyl-hydrazone (CCCP)], the proliferative effect of the He-Ne laser on melanocytes was abolished and suppression of melanocyte growth was noted. CONCLUSIONS: In summary, we have demonstrated that the He-Ne laser imparts a growth stimulatory effect on functional melanocytes via mitochondria-related pathways and proposed that other minor pathways including DNA damage may also be inflicted by laser treatment on irradiated cells. More importantly, we have completed the repigmentation scheme of vitiligo brought about by He-Ne laser light in vitro and provided a solid theoretical basis regarding how the He-Ne laser induces recovery of vitiligo in vivo.

Association study between keratinocyte-derived growth factor gene polymorphisms and susceptibility to vitiligo vulgaris in a Taiwanese population: potential involvement of stem cell factor.

BACKGROUND: Vitiligo vulgaris is a depigmentary disorder resulting from the disappearance of functional melanocytes. Currently, the pathogenesis of this disorder remains obscure. OBJECTIVES: Genetic analysis of patients with vitilgo may provide important clues for elucidating the complex pathomechanisms involved in the disease process. Because dysfunctional keratinocytes have recently been implicated in the pathogenesis of vitiligo vulgaris, we conducted a case-control association study to investigate this phenomenon. PATIENTS AND METHODS: Fifty-one patients with vitiligo vulgaris and 118 healthy controls from Taiwan were recruited to investigate the association between relevant keratinocyte-related genes and the occurrence of vitiligo vulgaris. This study genotyped 11 single-nucleotide polymorphisms (SNPs) in five genes including stem cell factor (SCF, also known as KITLG), basic fibroblast growth factor (bFGF, also known as NuDT6), endothelin-1 (EDN1), hepatocyte growth factor (HGF) and stem cell growth factor (SCGF, also known as CLEC11A). RESULTS: Our results revealed that the A allele for SNP rs11104947 in the SCF gene and the T allele for SNP rs13866 in the SCGF gene were, respectively, associated with a 1.95- and a 2.14-fold risk of developing vitiligo vulgaris. A higher risk was also detected among subjects who carried the SCF rs995029/rs11104947 C/A haplotype (odds ratio = 2.45). Furthermore, the at-risk alleles for SCF rs11104947 (A allele) and for SCGF SNP rs13866 (T allele) were found to display a 7.92-fold increased gene-gene combined risk. No significant relationship between polymorphic frequency for genes bFGF, EDN1 as well as HGF and occurrence of vitiligo vulgaris was observed. CONCLUSIONS: These novel genetic findings provide new insights in relation to the mechanisms that might be involved in the development of vitiligo vulgaris.

Hyperglycaemic conditions hamper keratinocyte locomotion via sequential inhibition of distinct pathways: new insights on poor wound closure in patients with diabetes.

BACKGROUND: Diabetes mellitus (DM) is characterized by impaired insulin signalling, elevated plasma glucose, and predisposition towards complications involving several organs. A major complication of DM is impairment of wound healing. In the re-epithelialization process during wound healing, migration of keratinocytes is a crucial step. Our previous report demonstrated that keratinocytes cultured in hyperglycaemic media showed decreased cell mobility. OBJECTIVES: The current study aimed to explore the effects of high glucose on keratinocyte migration after different treatment durations. METHODS: Keratinocytes were cultivated for indicated time periods under various concentrations of glucose. Relevant assays including Transwell migration and in vitro wound scratch assays, flow cytometric analysis, matrix metalloproteinase-1 (MMP-1) activity assay, determination of mRNA expression and Western blotting were performed. RESULTS: We demonstrated that (i) keratinocyte motility progressively and significantly decreased; (ii) the keratinocyte activation marker K16 was significantly suppressed; (iii) expression of alpha2beta1 integrin and MMP-1, both crucial for keratinocyte locomotion on collagen type I, was significantly downregulated; and (iv) expression of the phosphorylated signal transducer and activator of transcription-1 significantly decreased after hyperglycaemic treatment. More specifically, different pathways become involved after prolonged duration of high glucose cultivation to reduce keratinocyte locomotion further. CONCLUSIONS: We have demonstrated that high glucose treatment results in progressive suppression of keratinocyte locomotion and elucidated the molecular mechanisms involved. These results provide a reasonable explanation for the poor wound healing seen in patients with DM.