{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T19:53:48Z","timestamp":1792785228731,"version":"4.5.0"},"reference-count":58,"publisher":"National Academy of Sciences","issue":"45","license":[{"start":{"date-parts":[[2023,10,31]],"date-time":"2023-10-31T00:00:00Z","timestamp":1698710400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"NIH","award":["AI 15614"],"award-info":[{"award-number":["AI 15614"]}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,11,7]]},"abstract":"<jats:p>\n                    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.,\n                    <jats:italic>Fzd5<\/jats:italic>\n                    ,\n                    <jats:italic>Ephb2<\/jats:italic>\n                    , and\n                    <jats:italic>Olfm4<\/jats:italic>\n                    ) 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-1\u03b2 which contribute to organoid growth. However, high concentrations of IL-1\u03b2 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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2306476120","type":"journal-article","created":{"date-parts":[[2023,10,31]],"date-time":"2023-10-31T14:07:30Z","timestamp":1698761250000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":10,"title":["IL-38 regulates intestinal stem cell homeostasis by inducing WNT signaling and beneficial IL-1\u03b2 secretion"],"prefix":"10.1073","volume":"120","author":[{"given":"Alberto","family":"Dinarello","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makenna","family":"May","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Colorado Anschutz Medical 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