Acceleration of melanocyte senescence by the proinflammatory cytokines IFNγ and TNFα impairs the repigmentation response of vitiligo patients to narrowband ultraviolet B (NBUVB) phototherapy.

Vitiligo is a chronic autoimmune disease characterized by the T helper 1 (Th1) cytokine-driven immune destruction of melanocytes (MCs). Although narrowband ultraviolet B (NBUVB) phototherapy has been proven to be an effective therapeutic option, the repigmentation response to that phototherapy varies greatly in different vitiligo patients. Here, we demonstrate that there is an increase of NBUVB-induced cellular senescence in vitiligo MCs exposed to Th1 cytokine interferon γ (IFNγ) and/or tumor necrosis factor α (TNFα) in lesional vitiligo skin from poor responders who had undergone NBUVB phototherapy. Supplementation with exogenous recombinant human stem cell factor (rhSCF) in the culture medium as well as the lentiviral vector-mediated overexpression of cKIT could prevent the MCs from the IFNγ/TNFα-accelerated cellular senescence. Mechanistic studies indicated that the reduced ratio of membrane-bound KIT (mKIT) to the soluble form of KIT (sKIT) is directly related to the cellular senescence of vitiligo MCs following exposure to IFNγ and TNFα. Furthermore, the matrix metalloprotease 9 (MMP9) inhibitor GM6001 attenuates the production of sKIT via the suppression of cKIT ectodomain shedding. Altogether, our study indicates that the presence of Th1 cytokines IFNγ and/or TNFα in the epidermal milieu might impair the repigmentation response of vitiligo patients to NBUVB phototherapy.

Heme oxygenase-1 expression protects melanocytes from stress-induced cell death: implications for vitiligo.

To study protection of melanocytes from stress-induced cell death by heme oxygenases during depigmentation and repigmentation in vitiligo, expression of isoforms 1 and 2 was studied in cultured control and patient melanocytes and normal skin explants exposed to UV or bleaching agent 4-TBP. Similarly, expression of heme oxygenases was followed in skin from vitiligo patients before and after PUVA treatment. Single and double immunostainings were used in combination with light and confocal microscopic analysis and Western blotting. Melanocyte expression of heme oxygenase 1 is upregulated, whereas heme oxygenase 2 is reduced in response to UV and 4-TBP. Upregulation of inducible heme oxygenase 1 was also observed in UV-treated explant cultures, in skin of successfully PUVA-treated patients and in melanocytes cultured from vitiligo non-lesional skin. Heme oxygenase encoding genes were subsequently cloned to study consequences of either gene product on cell viability, demonstrating that HO-1 but not HO-2 overexpression offers protection from stress-induced cell death in MTT assays. HO-1 expression by melanocytes may contribute to beneficial effects of UV treatment for vitiligo patients.