Dysfunction of glutathione S-transferase leads to excess 4-hydroxy-2-nonenal and H(2)O(2) and impaired cytokine pattern in cultured keratinocytes and blood of vitiligo patients.
Oxidative stress due to increased epidermal levels of H(2)O(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 H(2)O(2) 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 H(2)O(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-H(2)O(2)-based mechanism of dysregulation of cytokine-mediated keratinocyte-melanocyte interaction in vitiligo.
Kostyuk
Vladimir A
VA
Tissue Engineering and Cutaneous Pathophysiology Laboratory, Dermatology Research Institute (IDI IRCCS), Rome, Italy.
Potapovich
Alla I
AI
Cesareo
Eleonora
E
Brescia
Serena
S
Guerra
Liliana
L
Valacchi
Giuseppe
G
Pecorelli
Alessandra
A
Deeva
Irina B
IB
Raskovic
Desanka
D
De Luca
Chiara
C
Pastore
Saveria
S
Korkina
Liudmila G
LG
D000293:Adolescent; D000328:Adult; D000368:Aged; D000447:Aldehydes / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D002648:Child; D018920:Coculture Techniques; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004912:Erythrocytes / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000235:genetics; D015870:Gene Expression / Q000235:genetics / Q000528:radiation effects; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D008297:Male; D008544:Melanocytes / Q000166:cytology; D008875:Middle Aged; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D010084:Oxidation-Reduction; D010766:Phosphorylation / Q000528:radiation effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics; D013482:Superoxide Dismutase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014466:Ultraviolet Rays; D014820:Vitiligo / Q000097:blood* / Q000378:metabolism*; D055815:Young Adult
D000447:Aldehydes; D002374:Catalase; D016207:Cytokines; D048049:Extracellular Signal-Regulated MAP Kinases; D016222:Fibroblast Growth Factor 2; D005978:Glutathione; D019803:Glutathione Disulfide; D005982:Glutathione Transferase; D006861:Hydrogen Peroxide; D015850:Interleukin-6; D052247:Nitric Oxide Synthase Type II; D051057:Proto-Oncogene Proteins c-akt; D055748:SOXB1 Transcription Factors; D013482:Superoxide Dismutase; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; C496319:NOS2 protein, human; C413545:glutathione S-transferase T1; C484555:GSTA1 protein, human; C494918:AKT1 protein, human; C027576:4-hydroxy-2-nonenal