375 The chromatin architectural protein CTCF regulates expression of pro-inflammatory cytokines in the skin cells

Abstract

Increased evidence suggests that alterations in chromatin structure result in aberrant pro-inflammatory cytokines expression that leads to prolonged inflammatory responses. CCCTC-binding factor (CTCF) is a transcriptional repressor that insulates the expression of neighbouring genes and is involved in chromatin interactions between distal and proximal gene regulatory elements. However, the role of CTCF in the control of pro-inflammatory cytokines expression in the skin cells remains unknown. Here, we show that CTCF is expressed in the nuclei of normal human epidermal keratinocytes (NHEK) and dermal fibroblasts (DF), while its siRNA-mediated deficiency induces cell-type specific changes in pro-inflammatory gene expression. Knockdown of CTCF using siRNAs leads to significant reductions in the transcription of a number of pro-inflammatory genes (TNF, IL1B, IL12B, IL17A, IL19, IL23A, IL36A, CXCL8) in NHEK. In contrast, transcript levels of these genes were markedly up-regulated in CTCF-depleted DF. Furthermore, TNF-alpha treatment causes a more profound inhibitory effect on the CTCF expression in DF compared to NHEK. Finally, we show that CTCF is down-regulated in primary psoriatic fibroblasts compared to DF, while CTCF expression was not affected in psoriatic keratinocytes. Taken together, these data suggest that the chromatin architectural protein CTCF is involved in cell-type specific regulation of pro-inflammatory genes in the skin cells, which suggests its involvement in pathogenesis of inflammatory skin diseases such as psoriasis.