Fas‐FasL interaction in cytotoxic T cell‐mediated vitiligo: The role of lesional expression of tumor necrosis factor‐α and interferon‐γ in Fas‐mediated melanocyte apoptosis

• DOI: 10.1111/exd.14053
• Publication Date: 2019-11-01T18:35:33Z
• Authors: Haruki Jimbo; Hiroshi Nagai; Susumu Fujiwara; Noriko Shimoura; Chikako Nishigori
• Keywords: Male; 0303 health sciences; Fas Ligand Protein; Tumor Necrosis Factor-alpha; CASP8 and FADD-Like Apoptosis Regulating Protein; Apoptosis; Middle Aged; Baculoviral IAP Repeat-Containing 3 Protein; 3. Good health; TNF-Related Apoptosis-Inducing Ligand; Interferon-gamma; Mice; 03 medical and health sciences; Animals; Humans; Melanocytes; Myeloid Cell Leukemia Sequence 1 Protein; Female; Gene Silencing; RNA, Messenger; Cells, Cultured; Metabolic Networks and Pathways; T-Lymphocytes, Cytotoxic

AbstractVitiligo is an acquired skin depigmentation disorder resulting from the selective loss of epidermal melanocytes, and previous studies have suggested that a T lymphocyte‐mediated mechanism has a role in melanocyte loss. Although Fas‐Fas ligand (FasL) interactions are important for T lymphocytes to mediate cytotoxicity, there are only few reports examining the involvement of the Fas‐FasL pathway in vitiligo using in vivo mouse models. In addition, there have been no reports concerning Fas‐mediated apoptosis in human melanocytes in vitro. In this study, we found that the Fas‐mediated pathway is involved in cytotoxic T lymphocyte (CTL)‐dependent vitiligo in a mouse model and FasL‐induced apoptosis of human melanocytes. Tumor necrosis factor (TNF)‐α and interferon (IFN)‐γ, the expression levels of which have been reported to be elevated in lesional skin of patients with vitiligo, synergistically upregulated Fas expression on human melanocytes but inhibited the Fas‐mediated apoptosis. Treatment with TNF‐α and IFN‐γ synergistically upregulated the expression of the anti‐apoptotic genes, c‐IAP2, c‐FLIP and MCL1. A siRNA knock‐down study showed that c‐FLIP and MCL1, but not c‐IAP2, were involved in inducing synergistic inhibitory effects on Fas‐mediated apoptosis. Furthermore, we found that FasL and TNF‐related apoptosis‐inducing ligand (TRAIL) synergistically induced apoptosis on human melanocytes. In conclusion, our results suggest that the Fas‐FasL pathway is involved in CTL‐dependent vitiligo and the elevated expression levels of TNF‐α and IFN‐γ in lesional skin may act synergistically on melanocytes to suppress Fas‐mediated apoptosis.