608 Targeting CtBP-mediated proinflammatory gene transcription to treat skin inflammation

Abstract

Inflammatory skin diseases (ISDs) such as psoriasis and allergic contact dermatitis affects millions of people and poses a major public health burden. Aberrant cytokine production is a prominent characteristic of ISDs, although the molecular mechanisms underlying the imbalance between pro- and anti-inflammatory gene expression remain underexplored. C-terminal-binding protein (CtBP) 1 and 2 are transcriptional coregulators that repress diverse cellular processes. Our recently studies have uncovered a previously unrecognized proinflammatory role of CtBP in skin inflammation. CtBP1 overexpression in transgenic mouse keratinocytes causes a psoriasis-like phenotype including increased epidermal proliferation, immunocyte infiltration and proinflammatory cytokine expression in skin. Expression of the CtBPs is elevated in both human psoriatic skin lesions and the inflamed skin of two mouse ISD models, the imiquimod-induced psoriasis and the DNFB-induced contact hypersensitivity. Keratinocytes stimulated by imiquimod or DNFB exhibit transactivation of CtBP2 and CtBP-controlled proinflammatory genes that is accompanied by increased recruitment of CtBPs to the target promoters. Furthermore, we demonstrate that distinct CtBP-specific inhibitors can effectively suppress the expression of the CtBP target genes by evicting CtBPs from their target promoters and relieve symptoms of skin inflammation with topical treatment in both mouse ISD models. Together, these findings indicate that the CtBPs can promote skin inflammation by transactivating a select set of proinflammatory genes and suggest new avenues for therapeutic modulation of inflammation and immune responses in ISDs.