TY - JOUR
T1 - 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
AU - Kostyuk, Vladimir A.
AU - Potapovich, Alla I.
AU - Cesareo, Eleonora
AU - Brescia, Serena
AU - Guerra, Liliana
AU - Valacchi, Giuseppe
AU - Pecorelli, Alessandra
AU - Deeva, Irina B.
AU - Raskovic, Desanka
AU - De Luca, Chiara
AU - Pastore, Saveria
AU - Korkina, Liudmila G.
PY - 2010/9/1
Y1 - 2010/9/1
N2 - 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.
AB - 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.
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U2 - 10.1089/ars.2009.2976
DO - 10.1089/ars.2009.2976
M3 - Article
C2 - 20070240
AN - SCOPUS:77953494073
VL - 13
SP - 607
EP - 620
JO - Antioxidants and Redox Signaling
JF - Antioxidants and Redox Signaling
SN - 1523-0864
IS - 5
ER -