Abstract
Psoriasis is a chronic inflammatory skin disease characterized by altered proliferation and differentiation of keratinocytes as well as infiltration of immune cells. Increased expression of Th17 cells and cytokines secreted by them provides evidence for its central role in the pathogenesis of psoriasis. IL-17A, signature cytokine of Th17 cells was found to be highly differentially expressed in psoriatic lesional skin. However, cellular and molecular mechanism by which IL-17A exerts its function on keratinocyte is incompletely understood. To understand IL-17A mediated signal transduction pathways, gene expression profiling was done and differentially expressed genes were analysed by IPA software. Here, we demonstrate that during IL-17A signaling total cholesterol levels were elevated, which in turn resulted in the suppression of genes of cholesterol and fatty acid biosynthesis. We found that accumulation of cholesterol was essential for IL-17A signaling as reduced total cholesterol levels by methyl β cyclodextrin (MBCD), significantly decreased IL-17A induced secretion of CCL20, IL-8 and S100A7 from the keratinocytes. To our knowledge this study for the first time unveils that high level of intracellular cholesterol plays a crucial role in IL-17A signaling in keratinocytes and may explain the strong association between psoriasis and dyslipidemia.
Highlights
Psoriasis is a chronic inflammatory skin disease with 2–3% prevalence worldwide
Comparison of gene expression for the cytokines secreted by Th17 cells (IL-24, IL-21, IL-22, TNF-α, IL-17A), cytokines involved in Th17 differentiation (IL-23, IL-21) and cytokines regulating Th17 cytokine response (OPN) and different members of IL-17 family (IL-17A, IL-17B, IL-17C) were further done by quantitative real time PCR (Q-RT PCR)
We found significant up regulation of TNF-α (2 fold), IL-24 (9 fold), IL-21 (3.5 fold), IL-17A (11.5 fold), IL-17B (1.5 fold), IL-17C (6.6 fold), IL-22 (9.5 fold), IL-23 (3.6 fold) and OPN (4 fold) in the psoriatic lesional skin as compared to non lesional skin (Fig. 1B)
Summary
Psoriasis is a chronic inflammatory skin disease with 2–3% prevalence worldwide. It is characterized by the erythematosquamous plaques, formed due to hyper proliferation and abnormal differentiation of keratinocytes as well as infiltration of immune cells[1]. This disease has an incompletely defined etiology. Multiple genome wide linkage studies revealed the association of polymorphisms in keratinocyte differentiation genes and the genes encoding the components of immune system with psoriasis[2]. Psoriasis is defined as a Th1/Th17 based inflammatory disease[5] It involves a crosstalk between immune cells including dendritic and T-cells with keratinocytes[6]. We describe a previously unidentified mode of action of IL-17A potentially opening new avenues for the treatment of psoriasis
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