Papoutsopoulou, Stamatia 
ORCID: 0000-0001-6665-8508, Pollock, Liam, Walker, Catherine, Tench, William, Samad, Sakim Shakh, Bergey, Francois, Lenzi, Luca ORCID: 0000-0003-2697-691X, Sheibani-Tezerji, Raheleh, Rosenstiel, Phillip, Alam, Mohammad Tauqeer et al (show 3 more authors)
(2021)
Impact of Interleukin 10 Deficiency on Intestinal Epithelium Responses to Inflammatory Signals.
FRONTIERS IN IMMUNOLOGY, 12.
690817-.
Abstract
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 has been extensively studied, its intrinsic role in intestinal epithelial cells is poorly understood. In this study, we utilised both ATAC sequencing 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 to TNF within intestinal epithelium were NF<i>κ</i>B transcription factor dependent. Using wild-type and <i>Il10<sup>-/-</sup></i> enteroid cultures, we showed an intrinsic, intestinal epithelium specific effect of IL-10 deficiency on TNF-induced gene transcription, with significant downregulation of identified NF<i>κ</i>B target genes <i>Tnf</i>, <i>Ccl20</i>, and <i>Cxcl10</i>, and delayed overexpression of NF<i>κ</i>B inhibitor encoding genes, <i>Nfkbia</i> and <i>Tnfaip3</i>. IL-10 deficiency, or immunoblockade of IL-10 receptor, impacted on TNF-induced endogenous NF<i>κ</i>B activity and downstream NF<i>κ</i>B target gene transcription. Intestinal epithelium-derived IL-10 appears to play a crucial role as a positive regulator of the canonical NF<i>κ</i>B pathway, contributing to maintenance of intestinal homeostasis. This is particularly important in the context of an inflammatory environment and highlights the potential for future tissue-targeted IL-10 therapeutic intervention.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | intestine, enteroids, interleukin 10, tumour necrosis factor, NF kappa B |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Infection, Veterinary and Ecological Sciences |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 01 Jul 2021 13:59 |
| Last Modified: | 18 Jan 2023 21:37 |
| DOI: | 10.3389/fimmu.2021.690817 |
| Open Access URL: | https://doi.org/10.3389/fimmu.2021.690817 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3128429 |
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