Dataset Information

Vitiligo-inducing phenols activate the unfolded protein response in melanocytes resulting in upregulation of IL6 and IL8.

ABSTRACT: Vitiligo is characterized by depigmented skin patches caused by loss of epidermal melanocytes. Oxidative stress may have a role in vitiligo onset, while autoimmunity contributes to disease progression. In this study, we sought to identify mechanisms that link disease triggers and spreading of lesions. A hallmark of melanocytes at the periphery of vitiligo lesions is dilation of the endoplasmic reticulum (ER). We hypothesized that oxidative stress results in redox disruptions that extend to the ER, causing accumulation of misfolded peptides, which activates the unfolded protein response (UPR). We used 4-tertiary butyl phenol and monobenzyl ether of hydroquinone, known triggers of vitiligo. We show that expression of key UPR components, including the transcription factor X-box-binding protein 1 (XBP1), is increased following exposure of melanocytes to phenols. XBP1 activation increases production of immune mediators IL6 and IL8. Co-treatment with XBP1 inhibitors reduced IL6 and IL8 production induced by phenols, while overexpression of XBP1 alone increased their expression. Thus, melanocytes themselves produce cytokines associated with activation of an immune response following exposure to chemical triggers of vitiligo. These results expand our understanding of the mechanisms underlying melanocyte loss in vitiligo and pathways linking environmental stressors and autoimmunity.

SUBMITTER: Toosi S

PROVIDER: S-EPMC3443495 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Vitiligo-inducing phenols activate the unfolded protein response in melanocytes resulting in upregulation of IL6 and IL8.

Toosi Siavash S Orlow Seth J SJ Manga Prashiela P

The Journal of investigative dermatology 20120614 11

Vitiligo is characterized by depigmented skin patches caused by loss of epidermal melanocytes. Oxidative stress may have a role in vitiligo onset, while autoimmunity contributes to disease progression. In this study, we sought to identify mechanisms that link disease triggers and spreading of lesions. A hallmark of melanocytes at the periphery of vitiligo lesions is dilation of the endoplasmic reticulum (ER). We hypothesized that oxidative stress results in redox disruptions that extend to the E ...[more]

PMID: 22696056

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Project description:Purpose: In order to explore the mechanism of hydroxychloroquine (HCQ) in treating vitiligo. We report the application of transcriptome profiling (RNA-seq) in human vitiligo melanocytes cell line PIG3V after HCQ treatment. Methods: The PIG3V cells were divided randomly in two groups: HCQ treatment (1 μg/mL, 24 hours) and the cells without treatment (only medium). RNA samples extracted from PIG3V cells were quantified by NanoDrop and Bioanalyzer. After 2 rounds of purification Poly A RNA was extracted then from total RNA by using Dynabeads Oligo. Small pieces of Poly A RNA were returned through Magnesium RNA Fragmentation Module under the condition of 94℃ for 5 minutes. Subsequently, SuperScript Reverse Transcriptase was used to reverse-transcribe the cleaved RNA pieces into cDNA. Then, U-labeled second-stranded DNAs was synthesized. After adding of A-base to each strand, preparing for indexed adapters, and heat-labile UDG enzyme treatment, PCR amplification was performed under (1) 95℃, 3 minutes; (2) 98℃, 15 seconds for 8 cycles; (3) 60℃, 15 seconds, 72℃, 5 minutes. Ultimately, RNA sequencing was performed according to protocol of Illumina Novaseq™ 6000 (LC-Bio Technology CO., Ltd., Hangzhou, China). After calculation, differential expressed genes were screened by fold change (FC)＞2 or FC＜0.5 and p value＜0.05. Results: Using an optimized data analysis workflow, we mapped about 30 million sequence reads per sample and identified 60612 genes and 229420 transcripts. Approximately 0.3% of the genes showed differential expression between the HCQ treated PIG3V cells and the cells without HCQ, with a fold change＞2 or＜0.5 , p value＜0.05. Conclusions: Our research showed the first detailed transcriptome analysis of human vitiligo melanocytes PIG3V, with or without HCQ treatment. We conclude that RNA-seq based transcriptome characterization would expedite genetic network analyses and permit the dissection of complex biologic mechanisms of HCQ in treating vitiligo.

Project description:BackgroundTranscription factor EGR3 (Early Growth Response 3) is a little-studied member of the EGR family that is highly expressed in human prostate tumours compared with normal tissue. Its function in prostate cancer, however, is unknown.MethodsStable shRNA silencing was achieved in naturally overexpressing prostate cancer cells, followed by Affymetrix expression analysis. Fold changes of ⩾2 and ⩽-2 were considered valid and t-tests P-values of ⩽0.01 were considered statistically significant. Potential EGR3 target genes were validated by real-time qPCR, chromatin immunoprecipitation, and gain-of-function experiments. Promoter analysis confirmed the presence of consensus binding sites in the promoters of target genes.ResultsEarly Growth Response 3 regulates the expression of ∼330 genes, 35% of which are involved in immune responses and inflammatory processes, and 15% crosstalk with the NF-κB signalling pathway. In particular, EGR3 induces the expression of over 50 secreted cytokines, growth factors, and matrix remodelling factors. Two interleukins of great relevance to prostate cancer, IL6 and IL8, were further validated as EGR3 target genes: both promoters contain EGR consensus binding sites and are pulled down in intact cells by EGR3 chromatin immunoprecipitation. Silencing of EGR3 decreased IL6 and IL8 expression, whereas overexpression of EGR3 in nontransformed cells induced IL6 and IL8 expression.ConclusionsChronic inflammation plays a critical role in prostate cancer and elevated production of pro-inflammatory cytokines IL8 and IL6, in particular, contributes to disease progression and to the onset of castration resistance. It is shown for the first time that EGR3 is involved in the upregulation of both IL6 and IL8. Together with our previous observation that EGR3 is highly expressed in prostate tumours compared with normal tissue and strongly correlates with IL6 and IL8 expression in clinical samples, the present study suggests that EGR3 promotes excessive production of IL6 and IL8 observed during the progression of prostate cancer.

Dataset Information

Vitiligo-inducing phenols activate the unfolded protein response in melanocytes resulting in upregulation of IL6 and IL8.

Publications

Vitiligo-inducing phenols activate the unfolded protein response in melanocytes resulting in upregulation of IL6 and IL8.

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