{"doi":"10.1073/pnas.2306476120","title":"IL-38 regulates intestinal stem cell homeostasis by inducing WNT signaling and beneficial IL-1β secretion","abstract":"The IL-1 Family member IL-38 has been characterized primarily as an antiinflammatory cytokine in human and mouse models of systemic diseases. Here, we examined the role of IL-38 in the murine small intestine (SI). Immunostaining of SI revealed that IL-38 expression partially confines to intestinal stem cells. Cultures of intestinal organoids reveal IL-38 functions as a growth factor by increasing organoid size via inducing WNT3a. In contrast, organoids from IL-38-deficient mice develop more slowly. This reduction in size is likely due to the downregulation of intestinal stemness markers (i.e., Fzd5 , Ephb2 , and Olfm4 ) expression compared with wild-type organoids. The IL-38 binding to IL-1R6 and IL-1R9 is still a matter of debate. Therefore, to analyze the molecular mechanisms of IL-38 signaling, we also examined organoids from IL-1R9-deficient mice. Unexpectedly, these organoids, although significantly smaller than wild type, respond to IL-38, suggesting that IL-1R9 is not involved in IL-38 signaling in the stem cell crypt. Nevertheless, silencing of IL-1R6 disabled the organoid response to the growth property of IL-38, thus suggesting IL-1R6 as the main receptor used by IL-38 in the crypt compartment. In organoids from wild-type mice, IL-38 stimulation induced low concentrations of IL-1β which contribute to organoid growth. However, high concentrations of IL-1β have detrimental effects on the cultures that were prevented by treatment with recombinant IL-38. Overall, our data demonstrate an important regulatory function of IL-38 as a growth factor, and as an antiinflammatory molecule in the SI, maintaining homeostasis.","journal":"Proceedings of the National Academy of Sciences","year":2023,"id":364772,"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":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9597,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":897759,"name":"Makenna May","orcid":null,"position":1,"is_corresponding":false},{"id":322672,"name":"Jesús Amo‐Aparicio","orcid":"0000-0002-1294-6819","position":2,"is_corresponding":false},{"id":623884,"name":"Tania Azam","orcid":"0000-0001-9807-3272","position":3,"is_corresponding":false},{"id":706615,"name":"Joseph M. Gaballa","orcid":"0009-0009-5291-8669","position":4,"is_corresponding":false},{"id":235544,"name":"Carlo Marchetti","orcid":"0000-0002-0203-316X","position":5,"is_corresponding":false},{"id":1120342,"name":"Annachiara Tesoriere","orcid":null,"position":6,"is_corresponding":false},{"id":1120343,"name":"Rachele Ghirardo","orcid":null,"position":7,"is_corresponding":false},{"id":300021,"name":"Jasmina S. Redzic","orcid":null,"position":8,"is_corresponding":false},{"id":1120344,"name":"William S. Webber","orcid":null,"position":9,"is_corresponding":false},{"id":303831,"name":"Shaikh M. Atif","orcid":"0000-0002-7928-5365","position":10,"is_corresponding":false},{"id":404460,"name":"Suzhao Li","orcid":"0000-0001-8641-2759","position":11,"is_corresponding":false},{"id":297840,"name":"Elan Eisenmesser","orcid":"0000-0002-6967-0892","position":12,"is_corresponding":false},{"id":481608,"name":"Dennis M. de Graaf","orcid":"0000-0002-9198-7159","position":13,"is_corresponding":false},{"id":235545,"name":"Charles A. Dinarello","orcid":"0000-0002-5073-8316","position":14,"is_corresponding":false},{"id":631842,"name":"Alberto Dinarello","orcid":"0000-0003-3124-7236","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-19T01:14:41.218128Z","pmid":"37906644","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":[]}