Injury to the ocular surface provokes an inflammatory response that is mediated, at least in part, by corneal epithelial derived 12-hydroxyeicosanoids (HETEs) including 12-HETE and 12-HETrE; both metabolites exhibit potent inflammatory and angiogenic properties and are formed by a cytochrome P450 (CYP) 4B1. Retinoids are known to mediate wound-healing processes in many tissues and, as such, are integral components of the inflammatory response. We studied the effect of various retinoids on corneal synthesis of 12-hydroxyeicosanoids and on activation of CYP4B1 gene expression. Corneal organ cultures were used to assess the effect of retinoic acid on epithelial metabolism of arachidonic acid to 12-hydroxyeicosanoids. Luciferase reporter vectors containing different lengths of the CYP4B1 3.4 kb-5'-untranslated region were used to examine the effect of vitamin D and retinoids (9-cis-retinoic acid and all-trans retinoic acid) on transcriptional activation of CYP4B1 in transient transfection experiments with HepG2 cells. Vitamin D had no effect on CYP4B1 promoter activity, but 9-cis and all-trans retinoic acids increased promoter activity by up to 70% over control. Addition of both 9-cis and all-trans retinoic acids resulted in an additive effect increasing promoter activity by 2-fold. The increased promoter activity correlated with the presence of RAR/RXR binding motifs. Incubation of corneal organ culture for 24 hours in the presence of 9-cis and all-trans retinoic acids increased the synthesis of 12-HETE and 12-HETrE by 2-fold. The finding that retinoic acid increases the expression of the CYP4B1 gene and enhances production of the inflammatory 12-hydroxyeicosanoids in the corneal epithelium may provide a linkage between wound healing and inflammation in the ocular surface.

Psoriasis is a common inflammatory skin disease with complex etiology and chronic progression. To provide novel insights into the regulatory molecular mechanisms of the disease, we performed RNA sequencing analysis of 14 pairs of skin samples collected from patients with psoriasis. Subsequent pathway analysis and extraction of the transcriptional regulators governing psoriasis-associated pathways was executed using a combination of the MetaCore Interactome enrichment tool and the cisExpress algorithm, followed by comparison to a set of previously described psoriasis response elements. A comparative approach allowed us to identify 42 core transcriptional regulators of the disease associated with inflammation (NFκB, IRF9, JUN, FOS, SRF), the activity of T cells in psoriatic lesions (STAT6, FOXP3, NFATC2, GATA3, TCF7, RUNX1), the hyperproliferation and migration of keratinocytes (JUN, FOS, NFIB, TFAP2A, TFAP2C) and lipid metabolism (TFAP2, RARA, VDR). In addition to the core regulators, we identified 38 transcription factors previously not associated with the disease that can clarify the pathogenesis of psoriasis. To illustrate these findings, we analyzed the regulatory role of one of the identified transcription factors (TFs), FOXA1. Using ChIP-seq and RNA-seq data, we concluded that the atypical expression of the FOXA1 TF is an important player in the disease as it inhibits the maturation of naive T cells into the (CD4+FOXA1+CD47+CD69+PD-L1(hi)FOXP3−) regulatory T cell subpopulation, therefore contributing to the development of psoriatic skin lesions.

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