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Ultraviolet (UV) A- and UVB-induced redox alterations and activation of nuclear factor-kappaB in human melanocytes - protective effects of alpha-tocopherol
Linköping University, Department of Clinical and Experimental Medicine, Dermatology and Venerology . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences.ORCID iD: 0000-0003-4075-159X
Linköping University, Department of Clinical and Experimental Medicine, Dermatology and Venerology . Linköping University, Faculty of Health Sciences.
2006 (English)In: British Journal of Dermatology, ISSN 0007-0963, Vol. 155, no 2, 292-300 p.Article in journal (Refereed) Published
Abstract [en]

Background Despite compelling evidence that ultraviolet (UV) irradiation causes melanoma the knowledge concerning reaction pathways and signalling transduction in melanocytes is still limited.

Objectives To evaluate the protective capacity of α-tocopherol and β-carotene during UVA and UVB irradiation of human melanocytes in vitro.

Methods Primary cultures of normal human melanocytes were irradiated by different wavelengths within the UV spectrum (UVA 6 J cm−2, UVB 60 mJ cm−2). Redox alterations and apoptosis were studied and the protective potential of α-tocopherol and β-carotene was evaluated.

Results UVA and UVB irradiation decreased the intracellular concentration of reduced glutathione and activated the transcription factor nuclear factor (NF)-κB, detected as the increased level of the p65 subunit and translocation to the nucleus. This coincided with a rise in the level of γ-glutamyl-cysteine-synthetase, the rate-limiting enzyme of the glutathione synthesis. UVA and UVB caused apoptotic cell death as detected by nuclear fragmentation and caspase activation 24 h postirradiation. Pretreatment with α-tocopherol prevented UVA- and UVB-induced glutathione loss, NF-κB translocation and diminished apoptosis, but β-carotene did not show a similar protective capacity. Further, exposure to α-tocopherol by itself reduced cell proliferation rate.

Conclusions UVA and UVB irradiation affected the intracellular redox state and increased the frequency of apoptosis in human melanocytes in vitro. α-Tocopherol might be a useful substance in protecting melanocytes from UV-induced damage.

Place, publisher, year, edition, pages
2006. Vol. 155, no 2, 292-300 p.
Keyword [en]
α-tocopherol, β-carotene, melanocyte nuclear factor-κB, reduced glutathione (GSH), ultraviolet A, ultraviolet B
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-14498DOI: 10.1111/j.1365-2133.2006.07347.xOAI: oai:DiVA.org:liu-14498DiVA: diva2:23597
Available from: 2008-11-14 Created: 2008-11-14 Last updated: 2017-08-30
In thesis
1. UVA/B induced redox alterations and apoptosis in human melanocytes
Open this publication in new window or tab >>UVA/B induced redox alterations and apoptosis in human melanocytes
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Malignant melanoma is one of the most rapidly increasing cancers and accounts for about three-quarter of all skin cancer deaths worldwide. Despite compelling evidence that ultraviolet (UV) irradiation causes melanoma the knowledge how various wavelength spectra affect the balance between proliferation and apoptosis controlling the homeostasis of the melanocyte population is still limited. The aim of this thesis was to elucidate the regulation of UVA/B induced apoptotic signaling in human epidermal melanocytes in vitro in relation to redox alterations and antioxidant photoprotection.

UVA irradiation induced changes in plasma membrane stability, decreased cell proliferation and increased apoptosis. In comparison, melanocyte plasma membrane was markedly resistant to UVB irradiation although apoptosis was triggered. Thus, UVA irradiation should not be overlooked as an etiologic factor in melanoma development. Further, after irradiation with UVA/B we found alterations in redox state manifested by a reduction of intracellular GSH levels, translocation of nuclear factor-κB from the cytosol to the nucleus, an increase of γ-glutamylcysteine synthetase, the rate-limiting enzyme in GSH synthesis, and an increased apoptosis frequency. α-Tocopherol provided photoprotection through several modes of action affecting redox alterations and signaling, stabilizing the plasma membrane, and decreased proliferation and apoptosis rate, while β-carotene did not show the same protective capacity. Altogether, α-tocopherol might be a useful substance in protecting melanocytes from UV induced damage.

We demonstrate UVA/B irradiation to activate the intrinsic pathway of apoptosis in melanocytes where translocation of Bcl-2 family proteins to the mitochondria modulates the apoptosis signal. Interestingly, the anti-apoptotic Bcl-2 family proteins generally thought to be attached to membranes, were localized in the cytosol before UV irradiation and translocated to the mitochondria in the surviving population, which might be a critical event in preventing apoptotic cell death. Lysosomal cathepsins were released to the cytosol acting as pro-apoptotic mediators upstream of activation and translocation of Bax to the mitochondria. When melanocytes were exposed to UVA, p53 participated in apoptosis regulation through interaction with Bcl-2 family proteins, while UVB induced p53-transcriptional activity and apoptosis involving lysosomal membrane permeabilization. Thus, depending on the UV wavelength p53 mediated apoptosis in melanocytes by transcriptional dependent or independent activity. These results emphasize p53 as an important pro-apoptotic component in the regulation of apoptosis.

This thesis gives new insight in the harmful and various effects of different wavelengths within the UV spectrum on human melanocytes in vitro. Improved knowledge of the apoptosis regulatory systems in melanocytes might lead to a better understanding of the formation of pigment nevi and malignant melanoma and, in the future, provide better strategies to prevent and eliminate tumor development and progression.

Place, publisher, year, edition, pages
Institutionen för biomedicin och kirurgi, 2007. 58 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1004
Keyword
UV, melanocyte, apoptosis, glutathione, p53
National Category
Dermatology and Venereal Diseases
Identifiers
urn:nbn:se:liu:diva-8880 (URN)978-91-85831-84-5 (ISBN)
Public defence
2007-06-05, Berzeliussalen, Campus US, Ingång 65, Hälsouniversitetet, Linköpings universitet, SE-581 85 Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2007-05-21 Created: 2007-05-21 Last updated: 2017-08-30

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Larsson Wäster, PetraÖllinger, KarinRosdahl, Inger

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