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Lac water extract inhibits IFN-γ signaling through JAK2-STAT1-IRF1 axis in human melanoma

Li, Luhui, Yokoyama, Satoru, Han, Na, Hayakawa, Yoshihiro
RSC advances 2018 v.8 no.38 pp. 21534-21540
acids, adverse effects, autoimmune diseases, cytokines, immunosuppression, infectious diseases, interferon-gamma, major histocompatibility complex, melanoma, monitoring, neoplasm cells, pathogenesis
Interferon-γ (IFN-γ) is a cytokine that plays an important role in the host defense of infectious diseases and in immune surveillance during tumor development; however, it has adverse effects in the pathogenesis of autoimmune diseases and in immunosuppressive microenvironments, promoting the immunoevasion of cancer cells. In this study, we identified lac water extract (Lac) as a candidate that can suppress IFN-γ signaling amongst 112 types of natural products, using PD-L1 promoter as a readout for the IFN-γ signaling. Moreover, we determined that Lac inhibits IFN-γ-induced PD-L1 and MHC class I expression on the cell surface in melanoma cells, both of which have been identified as the downstream molecules of IFN-γ signaling. We also determined that Lac inhibited the JAK2-STAT1-IRF1 pathway. Finally, we identified laccaic acids, encompassing laccaic acid A, B, C, and E, as the active components in Lac that inhibit IFN-γ signaling. Collectively, the laccaic acids are lead compounds for a novel inhibitor that targets the JAK2-STAT1-IRF1 pathway for diseases caused by the aberrant activation of IFN-γ signaling.