FRA1:c-JUN:HDAC1 complex down-regulates filaggrin expression upon TNF alpha and IFN gamma stimulation in keratinocytes

Filaggrin (FLG), an essential structural protein for skin barrier function, is downregulated under chronic inflammatory conditions, leading to disruption of the skin barrier. However, the detailed molecular mechanisms of how FLG changes in the context of chronic inflammation are poorly understood. Here, we identified the molecular mechanisms by which inflammatory cytokines inhibit FLG expression in the skin. We found that the AP1 response element within the -343/+25 of the FLG promoter was necessary for TNF alpha + IFN gamma-induced down-regulation of FLG promoter activity. Using DNA affinity precipitation assay, we observed that AP1 subunit composition binding to the FLG promoter was altered from c-FOS:c-JUN (at the early time) to FRA1:c-JUN (at the late time) in response to TNF alpha + IFN. stimulation. Knockdown of FRA1 or c-JUN abrogated TNF alpha + IFN gamma-induced FLG suppression. Histone deacetylase (HDAC) 1 interacted with FRA1:c-JUN under TNF alpha + IFN gamma stimulation. Knockdown of HDAC1 abrogated the inhibitory effect of TNF alpha + IFN gamma on FLG expression. The altered expression of FLG, FRA1, c-JUN, and HDAC1 was confirmed in mouse models of 2,4-dinitrochlorobenzene-induced atopic dermatitis and imiquimodinduced psoriasis. Thus, the current study demonstrates that TNFa + IFN. stimulation suppresses FLG expression by promoting the FRA1:c-JUN:HDAC1 complex. This study provides insight into future therapeutic strategies targeting the FRA1:c-JUN:HDAC1 complex to restore impaired FLG expression in chronic skin inflammation.