Transcriptional and Cytotoxic Responses of Human Intestinal Organoids to IFN Types I, II, and III. Immunohorizons 2022 Jul 05;6(7):416-429
Date
07/06/2022Pubmed ID
35790340Pubmed Central ID
PMC10243893DOI
10.4049/immunohorizons.2200025Scopus ID
2-s2.0-85133219101 (requires institutional sign-in at Scopus site) 13 CitationsAbstract
The three types of IFN have roles in antimicrobial immunity and inflammation that must be properly balanced to maintain tissue homeostasis. For example, IFNs are elevated in the context of inflammatory bowel disease and may synergize with inflammatory cytokines such as TNF-α to promote tissue damage. Prior studies suggest that in mouse intestinal epithelial cells (IECs), type III IFNs are preferentially produced during viral infections and are less cytotoxic than type I IFN. In this study, we generated human IEC organoid lines from biopsies of ileum, ascending colon, and sigmoid colon of three healthy subjects to establish the baseline responses of normal human IECs to types I, II, and III IFN. We found that all IFN types elicited responses that were qualitatively consistent across intestinal biopsy sites. However, IFN types differed in magnitude of STAT1 phosphorylation and identity of genes in their downstream transcriptional programs. Specifically, there was a core transcriptional module shared by IFN types, but types I and II IFN stimulated unique transcriptional modules beyond this core gene signature. The transcriptional modules of type I and II IFN included proapoptotic genes, and expression of these genes correlated with potentiation of TNF-α cytotoxicity. These data define the response profiles of healthy human IEC organoids across IFN types, and they suggest that cytotoxic effects mediated by TNF-α in inflamed tissues may be amplified by a simultaneous high-magnitude IFN response.
Author List
Constant DA, Van Winkle JA, VanderHoek E, Dekker SE, Sofia MA, Regner E, Modiano N, Tsikitis VL, Nice TJAuthor
Emilie Regner MD Assistant Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCytokines
Epithelial Cells
Humans
Intestines
Mice
Organoids
Tumor Necrosis Factor-alpha
