biostudies-literatureDinarello ANIAID NIH HHSNIHNIGMS NIH HHSNIH HHSe2306476120https://www.ebi.ac.uk/biostudies/studies/S-EPMC10636342biostudies-literatureUnknown120(45)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., <i>Fzd5</i>, <i>Ephb2</i>, and <i>Olfm4</i>) 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 mechProceedings of the National Academy of Sciences of the United States of AmericaIL-38 regulates intestinal stem cell homeostasis by inducing WNT signaling and beneficial IL-1β secretion.PMC10636342R01 GM139892R03 AI151651AI 15614R01 AI015614R56 AI015614R03 AI156560Amo-Aparicio JTesoriere Ade Graaf DMMarchetti CGhirardo RRedzic JSLi SAzam TAtif SMDinarello AMay MWebber WSEisenmesser EZGaballa JMDinarello CAfalseIL-38 regulates intestinal stem cell homeostasis by inducing WNT signaling and beneficial IL-1β secretion.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., <i>Fzd5</i>, <i>Ephb2</i>, and <i>Olfm4</i>) 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 mech2023-01-01T00:00:00Z2023 Nov2026-06-01T10:51:05.136Z2026-04-08T11:32:18.377ZS-EPMC106363423790664410.1073/pnas.2306476120