ABSTRACT
PURPOSE: To evaluate the regulating effect of Notch1 signaling on Th17/Treg immune imbalance in psoriasis vulgaris (PV). MATERIALS AND METHODS: Notch1, Hes-1, RORγt, Foxp3, IL-17, and IL-10 mRNA expression, as well as Th17 and Treg cell percentages in peripheral CD4+ T cells, were detected by real-time quantitative RT-PCR and flow cytometry, and serum concentrations of IL-17 and IL-10 were detected by ELISA in 36 PV patients and 32 healthy controls. Additionally, CD4+ T cells from 12 PV patients were treated with γ-secretase inhibitor DAPT, and the above indexes were measured. RESULTS: PV patients presented distinct Th17/Treg immune imbalance and highly expressed Notch1 and Hes-1 mRNA levels, which were positively correlated with psoriasis area and severity index (PASI) and the ratios of Th17/Treg and RORγt/Foxp3. DAPT treatment resulted in the obvious downregulation of Th17 cell percentage in cocultured CD4+ T cells, RORγt and IL-17 mRNA levels, and IL-17 concentration in cell-free supernatant from cocultured CD4+ T cells of PV patients in a dose-dependent manner, while there was no significant influence on Treg cell percentage, Foxp3, and IL-10 expression, therefore leading to the recovery of Th17/Treg immune imbalance. CONCLUSION: Notch1 signaling may contribute to the pathogenesis of PV by regulating Th17/Treg immune imbalance.
Subject(s)
Psoriasis/immunology , Psoriasis/metabolism , Receptor, Notch1/metabolism , T-Lymphocytes, Regulatory/metabolism , Th17 Cells/metabolism , Adolescent , Adult , Cell Polarity/drug effects , Diamines/pharmacology , Female , Flow Cytometry , Humans , Interleukin-10/genetics , Interleukin-10/metabolism , Interleukin-17/genetics , Interleukin-17/metabolism , Male , Middle Aged , Nuclear Receptor Subfamily 1, Group F, Member 3/genetics , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , Psoriasis/genetics , Real-Time Polymerase Chain Reaction , Receptor, Notch1/genetics , Signal Transduction/drug effects , Signal Transduction/genetics , T-Lymphocytes, Regulatory/drug effects , Th17 Cells/drug effects , Thiazoles/pharmacology , Transcription Factor HES-1/genetics , Transcription Factor HES-1/metabolism , Young AdultABSTRACT
Interleukin-17 (IL-17) is considered to play an important role in the pathogenesis of a number of inflammatory conditions. Previous studies demonstrated that intranasal injections of IL-17 resulted in pulmonary inflammation and lung damage, we therefore hypothesize that dexmedetomidine, a potent α2 adrenergic receptor agonist that shows anti-inflammation effects in several animal models of inflammation, would attenuate IL-17 induced lung injury. We examined the lung damage using a histological approach, and assessed the number of lung-infiltrating neutrophils in the bronchoalveolar lavage fluid. We then compared the production of selected cytokines by measuring their serum concentration after various treatments. Finally, we evaluated the expression of selected inflammatory genes and activation of NF-κB in the lung epithelial cells, using real-time PCR and western blot assay, respectively. In every aspect of pulmonary inflammation investigated, dexmedetomidine significantly and dose-dependently attenuated the inflammatory effects of IL-17. Our results not only give a comprehensive description of the protective action of dexmedetomidine on IL-17 induced acute lung injury, but also provide insights to the underlying cellular and molecular mechanisms.
Subject(s)
Acute Lung Injury/drug therapy , Adrenergic alpha-2 Receptor Agonists/therapeutic use , Anti-Inflammatory Agents/therapeutic use , Dexmedetomidine/therapeutic use , Epithelial Cells/immunology , Inflammation/drug therapy , Neutrophils/immunology , Animals , Bronchoalveolar Lavage Fluid/immunology , Cell Movement , Cells, Cultured , Cytokines/metabolism , Epithelial Cells/drug effects , Interleukin-17/metabolism , Lung/pathology , Mice , Mice, Inbred Strains , NF-kappa B/metabolism , Neutrophils/drug effectsABSTRACT
The insulin/insulin-like growth factor 1 (IGF-1) signaling pathway is evolutionary conserved in diverse species including C.elegans, saccharomyces cerevisiae, Drosophila melanogaster, rodents and humans, which is involved in many interrelated functions that are necessary for metabolism, growth and reproduction. Interestingly, more and more research has revealed that insulin/IGF-1 signaling pathway plays a pivotal role in the regulation of longevity. Generally, disruption of the power of this pathway will extend longevity in species ranging from C.elegans to humans. The role of insulin/IGF-1 in longevity is probably related to stress resistance. Although the underlying mechanisms of longevity are not fully understood, the Insulin/IGF-1 signaling pathway has attracted substantial attention and it will be a novel target to prevent or postpone age-related diseases and extend life span. In this review, we mainly focus on the similar constitution and role of insulin/IGF-1 signaling pathway in C.elegans, saccharomyces cerevisiae, rodents and humans.