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. 2020 Jul 29;21(15):5382. doi: 10.3390/ijms21155382

Figure 4.

Figure 4

Medicinal AHR/NRF2 dual agonists can restore the IL-4/IL-13-STAT6-induced downregulation of FLG, LOR, and IVL expression. Coal tar and glyteer activate AHR and inhibit the STAT6 effects partially by increasing the entry of OVOL1 into the nucleus. IL-4 and IL-13 activate dual oxidase protein 1 (DUOX1), generate reactive oxygen species (ROS) production, and promote STAT6 phosphorylation in keratinocytes. On the other hand, the activation or phosphorylation of STAT6 by IL-4 and IL-13 is negatively regulated by protein-tyrosine phosphatase, nonreceptor-type 1 (PTPN1) because PTPN1 dephosphorylates the phosphorylated STAT6. ROS induced by IL-4 and IL-13 inhibit PTPN1 activity and subsequently enhance STAT6 phosphorylation. AHR/NRF2 dual agonists also activate NRF2 and upregulate the antioxidative enzymes such as NAD(P)H quinone oxidoreductase 1 (NQO1) and heme oxygenase 1 (HMOX1), which neutralize the IL-4/IL-13-induced ROS and downregulate STAT6 phosphorylation by revitalizing the PTPN1 activity. IL-22, IL-24, and IL-17A also induce ROS production.