IMPACT OF INTERLEUKIN 10 DEFICIENCY ON INTESTINAL EPITHELIUM RESPONSES TO INFLAMMATORY SIGNALS

Interleukin-10 (IL-10) is a pleiotropic, anti-inflammatory cytokine that has a major protective role in the intestine. Although its production by cells of the innate and adaptive immune system have been extensively studied, its intrinsic role in intestinal epithelial cells is poorly understood. In this study, we utilised ATAC and RNA sequencing to define the transcriptional response of murine enteroids to tumour necrosis factor (TNF). We identified that the key early phase drivers of the transcriptional response within intestinal epithelium wereNFkB transcription factor dependent. TNF-induced Il10-/- enteroids showed significant downregulation of identified NFkB target genes Tnf and Ccl20, and delayed overexpression of genes encoding NFkB inhibitors, Nfkbia and Tnfaip3. Similar responses were observed in vivo. IL-10 deficiency also impacted on TNF-induced endogenous NFkB activation. Intestinal epithelium-derived IL-10 appears to play a crucial autocrine role in regulating NFkB-dependent transcriptional response to an inflammatory environment and a potential target for therapeutic intervention.