ABSTRACT
Psoriasis is a common chronic, immune-mediated inflammatory disease of the skin. PSORS1C3 is a non-protein coding gene, of which the RNA transcript is found in psoriatic patients. CARD14 is mainly expressed in epidermal keratinocytes. TLR4 is a transmembrane protein to recognize microbial antigens. Our study aimed to assess the relationship among PSORS1C3, CARD14 and TLR4 polymorphisms, inflammatory expression and psoriasis susceptibility. To the end, 71 patients with psoriasis and 46 healthy individuals with the well-characterized clinical profiles were enrolled. Gene polymorphisms were determined by Sanger DNA sequencing and secretion of cytokines by ELISA. As a result, genetic analysis of PSORS1C3 gene identified nine SNPs and three haplotype blocks. Sequencing of the CARD14 gene determined eight SNPs and one haplotype block. Sequencing of TLR4 gene identified nine SNPs, in which a SNP rs1018673641 was found to exert deleterious effect. The linkage disequilibrium analysis showed that seven variants in PSORS1C3 gene and three SNPs in CARD14 gene were in tightly linked. More importantly, a significant association between IL-6 level and rs1018673641 AT genotype in TLR4 gene was detected in psoriatic patients. In conclusion, the PSORS1C3, CARD14 and TLR4 polymorphisms and haplotypes may be correlated with risk of suffering psoriasis and the IL-6-mediated chronic inflammation in psoriasis could be partially regulated by the TLR4 functional variant.
ABSTRACT
BACKGROUND: Dendritic cells (DCs) are the most potent professional antigen-presenting cells for naive T cells to link innate and acquired immunity. Klotho, an anti-aging protein, participates in the regulation of Ca2+ dependent migration in DCs. Vitamin E (VitE) is an essential antioxidant to protect cells from damage and elicits its inhibitory effects on NF-κB-mediated inflammatory response. However, the roles of VitE on mouse DC functions and the contribution of klotho to those effects both are unknown. The present study explored the effects of VitE on klotho expression, maturation, ROS production and migration in DCs. METHODS: The mouse bone marrow cells were isolated and cultured with GM-CSF to attain bone marrow-derived DCs (BMDCs). Cells were stimulated with LPS (100 ng/ml) in the presence or absence of VitE (500 µM). RT-PCR and immunoprecipitation methods were employed to determine klotho expression, ELISA to determine cytokine release, flow cytometry to analyze number of CD86+CD11c+ cells, the intracellular expression of cytokines and reactive oxygen species (ROS) production and a transwell migration assay to trace migration. RESULTS: Klotho transcript level and this hormone secretion in DC supernatant were enhanced by VitE treatment and further increased in the presence of NF-κB inhibitor Bay 11-7082 (10 µM). Moreover, VitE treatment inhibited IL-12p70 protein expression of, ROS accumulation in and CCL21-dependent migration of LPS-triggered mature DCs, these effects were reversed following klotho silencing. CONCLUSION: The up-regulation of klotho by VitE could contribute to the inhibitory effects of VitE on NF-κB-mediated DC functional maturation. The events might contribute to immunotherapeutic effect of VitE on the pathophysiology of klotho-related disease.
Subject(s)
Dendritic Cells/drug effects , Glucuronidase/drug effects , Vitamin E/pharmacology , Vitamins/pharmacology , Analysis of Variance , Animals , Bone Marrow Cells/cytology , Cell Movement/drug effects , Dendritic Cells/physiology , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Glucuronidase/physiology , Immunoblotting , Interleukin-12/analysis , Intracellular Signaling Peptides and Proteins , Klotho Proteins , Lipopolysaccharides , Mice, Inbred BALB C , Proteins/analysis , Proteins/drug effects , Reactive Oxygen Species/metabolism , Real-Time Polymerase Chain Reaction , Reproducibility of Results , Time Factors , Tumor Necrosis Factor-alpha/analysis , Up-RegulationABSTRACT
BACKGROUND: Despite the availability of effective vaccines, hepatitis B virus (HBV) infection is still frequent worldwide, and accounts for significant morbidity and mortality. However, data of acute HBeAg negative hepatitis still remain limited. AIMS AND METHODS: To understand clinical pictures of acute HBV hepatitis and its natural evolution, a prospective study was conducted in adult patients. RESULTS: Ninety patients were enrolled between March 2004 and April 2005 at Hospital for Tropical Diseases in Ho Chi Minh city. The prevalence of HBeAg negative was 53%. No significant difference was found in clinical characteristics and laboratory findings between HBeAg positive and negative patients. HBV-DNA was detected in 75% and 88% HBe negative and positive patients, respectively, where the frequency of ALT below 400 U/L was significantly higher in HBeAg negative cases (p= 0.01). Six month follow-up was available in 47 patients. HBsAg positivity was found in 16% of HBeAg negative subjects but only in 4.5% of HBeAg positive cases. Thirty two patients had neither HBsAg nor anti-HBs. CONCLUSIONS: The clinical laboratory feature and the outcome at 6 months of HBV acute hepatitis in Vietnam is similar in HBeAg positive and negative patients.