{"doi":"10.4049/jimmunol.2200125","title":"Th17-Derived Cytokines Synergistically Enhance IL-17C Production by the Colonic Epithelium","abstract":"Tightly regulated communication between the gastrointestinal epithelium and immune cells in the underlying lamina propria is critical for immune homeostasis and inflammation. IL-17C, produced by epithelial cells after exposure to inflammatory stimuli, facilitates cell-to-cell communication by promoting inflammatory responses in Th17 cells. In this study, we demonstrate that Th17-derived cytokines TNF-α, IL-17A, and IL-22 synergistically enhance IL-17C expression in both human-transformed colonic epithelial cell lines and primary non-inflammatory bowel disease colonic epithelial spheroids. This synergistic expression requires activation of the transcription factor NF-κB downstream of the TNF-α stimulus, evidenced by the reduction of IL-17C expression in the presence of an IκBα inhibitor. IL-17A and IL-22 enhance IL-17C expression through the activation of the transcription factor AP-1 in a p38 MAPK-dependent manner. Colonic spheroids derived from uninvolved epithelial of ulcerative colitis patients stimulated with TNF-α, IL-17A, and IL-22 show muted responses compared with non-inflammatory bowel disease spheroids, and inflamed spheroids yielded more IL-17C expression in the presence of TNF-α, and no response to IL-22 stimulation. Altogether, a role for IL-17C in activating Th17 cells combined with our findings of Th17-derived cytokine-driven synergy in the expression of IL-17C identifies a novel inflammatory amplification loop in the gastrointestinal tract between epithelial cells and Th17 cells.","journal":"The Journal of Immunology","year":2022,"id":266090,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.956,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":674089,"name":"Abson Madola","orcid":"0000-0002-5976-3833","position":1,"is_corresponding":false},{"id":850614,"name":"Michelle A. Cruz","orcid":"0000-0002-6225-7173","position":2,"is_corresponding":false},{"id":926241,"name":"Braulio J. Llorens-Bonilla","orcid":null,"position":3,"is_corresponding":false},{"id":488640,"name":"Alan D. Levine","orcid":"0000-0002-5706-0667","position":4,"is_corresponding":false},{"id":674088,"name":"Stephanie M. Swedik","orcid":"0000-0001-8913-5590","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-19T00:26:54.081997Z","pmid":"36130829","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}