Dysfunction of glutathione s-transferase leads to excess 4-hydroxy-2-nonenal and h2o2 and impaired cytokine pattern in cultured keratinocytes and blood of vitiligo patients

Vladimir A. Kostyuk, Alla I. Potapovich, Eleonora Cesareo, Serena Brescia, Liliana Guerra, Giuseppe Valacchi, Alessandra Pecorelli, Irina B. Deeva, Desanka Raskovic, Chiara De Luca, Saveria Pastore, Liudmila G. Korkina

Research output: Contribution to journalArticle

Abstract

Oxidative stress due to increased epidermal levels of H2O 2 with consequent inhibition of catalase activity is generally accepted as a leading cytotoxic mechanism of melanocyte loss in vitiligo. Keratinocyte-derived cytokines are considered key factors in the maintenance of melanocyte structure and functions. We hypothesized that abnormal redox control may lead to impaired cytokine production by keratinocytes, thus causing noncytotoxic defects in melanocyte proliferation and melanogenesis. We found significantly suppressed mRNA and protein expression of glutathione-S- transferase (GST) M1 isoform, and higher-than-normal levels of both 4-hydroxy-2-nonenal (HNE)-protein adducts and H2O2 in the cultures of keratinocytes derived from unaffected and affected skin of vitiligo patients, and in their co-cultures with allogeneic melanocytes. GST and catalase activities, as well as glutathione levels, were dramatically low in erythrocytes, whilst HNE-protein adducts were high in the plasma of vitiligo patients. The broad spectrum of major cytokines, chemokines, and growth factors was dysregulated in both blood plasma and cultured keratinocytes of vitiligo patients, when compared to normal subjects. Exogenous HNE added to normal keratinocytes induced a vitiligo-like cytokine pattern, and H2O 2 overproduction accompanied by adaptive upregulation of catalase and GSTM1 genes, and transient inhibition of Erk1/2 and Akt phosphorylation. Based on these results, we suggest a novel GST-HNE-H2O2-based mechanism of dysregulation of cytokine-mediated keratinocyte-melanocyte interaction in vitiligo.

Original languageEnglish
Pages (from-to)607-620
Number of pages14
JournalAntioxidants and Redox Signaling
Volume13
Issue number5
DOIs
Publication statusPublished - Sep 1 2010

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Physiology
  • Clinical Biochemistry

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    Kostyuk, V. A., Potapovich, A. I., Cesareo, E., Brescia, S., Guerra, L., Valacchi, G., Pecorelli, A., Deeva, I. B., Raskovic, D., De Luca, C., Pastore, S., & Korkina, L. G. (2010). Dysfunction of glutathione s-transferase leads to excess 4-hydroxy-2-nonenal and h2o2 and impaired cytokine pattern in cultured keratinocytes and blood of vitiligo patients. Antioxidants and Redox Signaling, 13(5), 607-620. https://doi.org/10.1089/ars.2009.2976