17035 Transcriptome profiling of DPP-4–inhibited primary keratinocytes reveals the up-regulatory effect of DPP-4 inhibition on keratinocyte differentiation

Abstract

Dipeptidyl peptidase 4 (DPP-4) is widely expressed in keratinocytes as well as many other tissues. Although the impact of DPP-4 inhibition has been well characterized in systems, its direct impact on skin remains unclear. Recently, the use of DPP-4 inhibition is associated with an increased risk of developing bullous pemphigoid through what is thought to be an immune mediated mechanism. In contrast, DPP-4 inhibition appears beneficial in psoriasis. To elucidate the effect of DPP-4 inhibition in keratinocytes, we performed RNA-seq using a small molecular inhibitor of DPP-4. Primary keratinocytes were grown in serum free, low calcium media to subconfluence, and treated for 24 hours. Subsequntly, RNA was extracted, with subsequent quality control, enrichment, and library preparation. Sequencing was performed on an Illumina HiSeq PE150. We used DESeq to analyze differentially expressed genes and Gene Ontology (GO) for an enrichment analysis. Blockade of DPP4 resulted in 424 differentially expressed genes. GO analysis demonstrated significant impact on skin development, keratinocyte differentiation, and cornification. We noted significant up-regulation of late cornified envelope protein complex (LCE1A, LCE1B, LCE1C, LCE1D, LCE1F, LCE2A, LCE2B, LCE2D, LCE3A, LCE3D, LCE3E), small proline rich protein complex (SPRR2A, SPRR2B, SPRR2D, SPRR2E, SPRR2F, SPRR2G, SPRR3, SPRR4, SPRR5), S100 calcium-binding protein A7, peptidase inhibitor 3, and interleukin 36G. Results demonstrate a significant role of DPP-4 inhibition in altering the keratinocyte transcriptome, particularly epidermal differentiation. This effect on keratinocyte differentiation may account for the beneficial impact on psoriasis with use of DPP-4 inhibitors.