IL-22 promotes cell proliferation to combat virus infection in human intestinal epithelial cells

Interferon lambdas (IFN-?s) are crucial to control virus infections at mucosal surfaces. Interleukin-22 (IL-22) was reported to help IFN-? control rotavirus infection in mice either by aiding in the induction of interferon stimulated genes (ISGs) or by increasing cell proliferation thereby clearing virally infected cells. We investigated whether IL-22 and IFN-?s exhibited similar synergistic effects in human intestinal epithelial cells models. Our results showed that co-treatment of IL-22 and IFN-? induced more phosphorylation of STAT1 than either cytokine used alone. However, this increased STAT1 activation did not translate to increased ISG production or antiviral protection. Transcriptomics analysis revealed that despite sharing a receptor and activating the similar STATs, the signaling generated by IL-22 and IFN-?s is independent where IFN-?s signaling induces ISGs and IL-22 signaling induces cell proliferation genes. Using human intestinal organoids, we confirmed that IL-22 increased the size of the organoids due to increased cell proliferation and increasing the stem cell marker (OLFM4). These findings suggest that in human intestinal cells, IFN-?s and IL-22 act independently to clear virus infections. IFN-?s induce ISGs to control virus replication and spread while IL-22 increases cell proliferation to eliminate infected cells and repair the damage epithelium. Although, these two cytokines do not increase each other's function, they each play a key role in protecting human intestinal epithelium cells. Overall design: To investigate whether IL-22 or IFN-? induce distinct or unique genes, human colon carcinoma cells (T84) cells were mock treated or treated with 100ng/ml of each IFN-?1,2,and 3; 100ng/mL IL-22 or a combination of 100ng/mL of IFN-?1-3+ 100ng/mL IL-22. 3 biological replicates for each condition were collected at 3, 6, 12, and 24 hours post-treatment. Samples were analyzed for the gene upregulation as compared to mock treated.