hes1-protein--human and Psoriasis

Topics: Adalimumab; Anti-Inflammatory Agents; Cells, Cultured; Fibroblasts; Gene Expression; Humans; Interleukin-12; Interleukin-23; Interleukin-6; Leptin; MicroRNAs; Psoriasis; Receptors, Notch; RNA, Messenger; Signal Transduction; Transcription Factor HES-1; Transcription, Genetic

Psoriasis is a chronic inflammatory skin disease, characterized by hyperproliferation of keratinocytes and by skin infiltration of activated T cells. To date, the pathophysiology of psoriasis has not yet been fully elucidated. The Notch pathway plays a determinant role in cell fate determination, proliferation, differentiation, immune cell development and function. Many biological agents, used in the treatment of psoriasis, include TFN-α inhibitors, such as etanercept, adalimumab, and anti IL-12/IL-23 p40 antibody, such as ustekinumab. This study aimed to determine mRNA expression levels by real-time RT-PCR, and protein expression levels, analysed by Western blot and immunohistochemistry, of some components of the Notch pathway, such as NOTCH1, NOTCH2, JAGGED1, and HES1 after biological treatments in psoriatic patients. mRNA and protein levels of NOTCH1, NOTCH2, JAGGED1 and HES1 were upregulated in skin samples from untreated psoriatic patients compared with normal controls. Biological therapy showed to downregulate differently the protein expression levels of the molecules under study. Our study suggests that Notch pathway components might be a potential therapeutic target against psoriasis.

Topics: Adalimumab; Adult; Aged; Anti-Inflammatory Agents; Basic Helix-Loop-Helix Transcription Factors; Biological Therapy; Calcium-Binding Proteins; Etanercept; Female; Homeodomain Proteins; Humans; Intercellular Signaling Peptides and Proteins; Interleukin-12 Subunit p40; Jagged-1 Protein; Keratinocytes; Male; Membrane Proteins; Middle Aged; Psoriasis; Receptor, Notch1; Receptor, Notch2; RNA, Messenger; Serrate-Jagged Proteins; Skin; Transcription Factor HES-1; Tumor Necrosis Factor-alpha; Ustekinumab

Psoriasis is an autoimmune disease mediated mainly by dysfunctional peripheral blood T cells. Both CD4+/CD8+ T cells and CD4+CD25+ regulatory T cells derived from psoriatic CD34+ bone marrow cells in vitro have been found to be functionally similar to those psoriatic circulating and lesional T cells. Notch signaling participates in diverse cell fate decisions during T cell development and has been reported to influence the proliferation of hematopoietic stem cells and the differentiation of T cells. The purpose of this study was to investigate the expression levels of Notch receptor 1, 2 and its target gene Hes-1 in CD34+ cells from patients with psoriasis. The total RNA and protein of CD34+ cells were extracted, and the mRNA as well as protein expression of Notch1, Notch2 and Hes-1 were investigated using real-time PCR and Western blot assays. We found that the mRNA and protein expression levels of Notch1 and Hes-1 in psoriasis patients were higher compared to normal controls, while the Notch2 mRNA and protein expression levels in psoriasis patients were similar to those of normal controls. The elevated Notch1 and Hes-1 expression levels in psoriatic CD34+ cells might be one reason for the immune disorders which are mainly mediated by T cells.

Topics: Adult; Aged; Antigens, CD34; Basic Helix-Loop-Helix Transcription Factors; Bone Marrow Cells; Female; Gene Expression Regulation; Homeodomain Proteins; Humans; Male; Middle Aged; Psoriasis; Real-Time Polymerase Chain Reaction; Receptors, Notch; RNA, Messenger; Transcription Factor HES-1; Young Adult

Psoriasis is a chronic inflammatory disease of the skin. The dysfunctional immunity experienced by patients with psoriasis is believed to influence the bone marrow haematopoietic cells and their surrounding microenvironment. Phagocytes derived from the bone marrow of patients with active psoriasis exhibit enhanced monocytopoietic activity and hyperplasia in vitro. However, direct evidence supporting the hypothesis that bone marrow is involved in the pathogenesis of psoriasis has yet to be established.. To investigate the involvement of bone marrow in the pathogenesis of psoriasis.. Bone marrow mononuclear cells (BMMNCs) were isolated from patients with psoriasis and healthy individuals. The high proliferative potential colony-forming cells (HPP-CFCs), granulocyte-macrophage colony-forming units (CFU-GM) and erythroid colony-forming units (CFU-E) were cultured in the presence of defined cytokines, and the effects of secreted factors from psoriatic peripheral blood mononuclear cells (PBMCs) on colony formation of normal haematopoietic cells were analysed. Furthermore, the telomere activity of psoriatic and normal BMMNCs was determined using the polymerase chain reaction (PCR)-based telomeric repeat amplification protocol, while the expression of human telomerase reverse transcriptase (hTERT) and HES1 mRNA was detected by reverse transcription-PCR assay.. The numbers of HPP-CFCs and CFU-GM, but not CFU-E, were significantly reduced in cultured haematopoietic cells from patients with psoriasis. The culture supernatant of PBMCs from patients with psoriasis was found to inhibit the colony formation capacity of HPP-CFCs, CFU-GM and CFU-E of normal haematopoietic cells. We also detected low levels of telomerase activity and hTERT gene expression in psoriatic and control BMMNCs that was statistically similar between the two groups. In contrast, the HES1 gene expression appeared to be significantly elevated in psoriatic BMMNCs (P < 0.05).. Together, our results indicate the involvement of bone marrow in the immunopathogenesis of psoriasis, and suggest a mechanism mediated by certain inflammatory or haematopoietic cytokines present in the bone marrow microenvironment. Elevated expression levels of HES1 mRNA suggest a potential role for the Notch signalling pathway in this process.

Topics: Adolescent; Adult; Aged; Basic Helix-Loop-Helix Transcription Factors; Cells, Cultured; Female; Granulocyte-Macrophage Progenitor Cells; Hematopoietic Stem Cells; Homeodomain Proteins; Humans; Male; Middle Aged; Polymerase Chain Reaction; Psoriasis; RNA, Messenger; Severity of Illness Index; Telomerase; Transcription Factor HES-1; Young Adult