Upregulation of CD86 and IL-12 by rhododendrol in THP-1 cells cocultured with melanocytes through ROS and ATP. Issue 3 (December 2022)

• Record Type: Journal Article
• Authors: Katahira, Yasuhiro; Sakamoto, Eri; Watanabe, Aruma; Furusaka, Yuma; Inoue, Shinya; Hasegawa, Hideaki; Mizoguchi, Izuru; Yo, Kazuyuki; Yamaji, Fumiya; Toyoda, Akemi; Yoshimoto, Takayuki
• Is Part Of: Journal of dermatological science. Volume 108:Issue 3(2022)
• Page Start: 167
• Page End: 177
• Publication Date: 2022-12
• Subjects: AA ascorbic acid -- 7-AAD 7-aminoactinomycin D -- BBG Brilliant Blue G -- CTL cytotoxic CD8+T lymphocyte -- DC dendritic cell -- h-CLAT human cell line activation test -- h-CLATw/M h-CLAT cocultured with melanocytes -- h-CLATw/H h-CLAT cocultured with HaCaT cells -- GSK GSK2606414 -- HQ hydroquinone -- NAC N-acetyl-L-cysteine -- PERK protein kinase R-like endoplasmic reticulum kinase -- RD rhododendrol -- RFI relative fluorescence intensity -- RK raspberry ketone -- ROS reactive oxygen species -- SDS-PAGE sodium dodecyl sulfate-polyacrylamide gel electrophoresis -- TXA tranexamic acid; Rhododendrol -- Leukoderma -- Sensitizer -- Pro-hapten -- H-CLAT -- Melanocytes; Dermatology -- Periodicals; Skin Diseases -- Periodicals; Dermatologie -- Périodiques; 616.5005
• DOI: 10.1016/j.jdermsci.2022.12.012
• Languages: English
• ISSNs: 0923-1811

Abstract

Abstract: Background: The tyrosinase inhibitor rhododendrol (RD), used as a skin whitening agent, reportedly has the potential to induce leukoderma. Objective: Although an immune response toward melanocytes was demonstrated to be involved in leukoderma, the molecular mechanism is not fully understood. Methods: We hypothesized that if RD is a pro-hapten and tyrosinase-oxidized RD metabolites are melanocyte-specific sensitizers, the sensitizing process could be reproduced by the human cell line activation test (h-CLAT) cocultured with melanocytes (h-CLATw/M) composed of human DC THP-1 cells and melanoma SK-MEL-37 cells. Cell surface expression, ROS generation and ATP release, mRNA expression, and the effects of several inhibitors were examined. Results: When RD was added to the h-CLATw/M, the expression of cell-surface CD86 and IL-12 mRNA was greatly enhanced in THP-1 cells compared with those in the h-CLAT. The rapid death of melanoma cells was induced, with ROS generation and ATP release subsequently being greatly enhanced, resulting in the cooperative upregulation of CD86 and IL-12. Consistent with those observations, an ROS inhibitor, ATP receptor P2X7 antagonist, or PERK inhibitor antagonized the upregulation. CD86 upregulation was similarly observed with another leukoderma-inducible tyrosinase inhibitor, raspberry ketone, but not with the leukoderma noninducible skin-whitening agents ascorbic acid and tranexamic acid. Conclusion: RD is a pro-hapten sensitizer dependent on tyrosinase that induces ROS generation and ATP release from melanocytes for CD86 and IL-12 upregulation in DCs, possibly leading to the generation of tyrosinase-specific cytotoxic T lymphocytes. The coculture system h-CLATw/M may be useful for predicting the sensitizing potential to induce leukoderma. Highlights: A new h-CLATw/M composed of THP-1 cells and melanoma SK-MEL-37 cells was established. RD upregulates CD86 and IL-12 in THP-1 via ROS and ATP production from SK-MEL-37. h-CLATw/M can distinguish between leukoderma-inducible and non-inducible agents. RD is a pro-hapten dependent on tyrosinase, possibly leading to CTL generation. h-CLATw/M would be useful to predict the sensitizing potential to induce leukoderma.