{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T22:57:31Z","timestamp":1793228251617,"version":"4.5.0"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T00:00:00Z","timestamp":1750896000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Inflammatory bowel disease (IBD) is a multifactorial, chronic disease that affects approximately 1.5 million people in the United States. Several important factors are implicated in the pathogenesis of IBD, one factor being dysregulation of the immune system. This dysregulation results in the accumulation and stimulation of innate and adaptive immune cells, and subsequent release of soluble factors, including pro-inflammatory cytokines. One of these cytokines is a member of the IL-36 cytokine family, IL-36\u03b3, which is overexpressed in human IBD and experimental models of colitis. In this study, we explored the role of IL-36\u03b3 in promoting CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cell activation and cytokine secretion.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Spleens and lymph nodes were collected from wild-type and IFN\u03b3\n                      <jats:sup>-\/-<\/jats:sup>\n                      mice and were processed into cell suspensions to isolate na\u00efve CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells. Na\u00efve CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells were stimulated with IL-36 cytokines. IFN\u03b3 and TNF\u03b1 were evaluated by ELISA using cell culture supernatants, and cell culture pellets were used to isolate RNA for qPCR. Na\u00efve CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells previously stimulated in the presence or absence of IL-36\u03b3, from wild type (WT) or IFN\u03b3-\/- mice were transferred to Rag-\/- mice to induce colitis. Fecal pellets were collected from mice during disease to analyze lipocalin (LCN2) levels from fecal supernatants. After euthanasia, colons, spleens, and mesenteric lymph nodes were harvested and processed into cell suspensions for intracellular cytokine staining.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Our results demonstrate that IL-36\u03b3 stimulation of naive CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells significantly induced IFN\u03b3 expression\n                      <jats:italic>in vitro<\/jats:italic>\n                      and was associated with augmented intestinal inflammation\n                      <jats:italic>in vivo<\/jats:italic>\n                      using the T cell transfer model of colitis. Using IFN\u03b3\n                      <jats:sup>-\/-<\/jats:sup>\n                      naive CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells, we observed a dramatic decrease in the ability of these cells to produce TNF\u03b1. Moreover, the transfer of these cells to Rag\n                      <jats:sup>-\/-<\/jats:sup>\n                      mice did not cause robust colitis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These data not only suggest that IL-36\u03b3 is a regulator of a pro-inflammatory cytokine network involving IFN\u03b3 and TNF\u03b1 but also highlights the importance of targeting IL-36\u03b3 and IFN\u03b3 as therapeutic approaches. Our studies have broad implications in relation to targeting specific cytokines in human IBD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1604332","type":"journal-article","created":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T01:27:53Z","timestamp":1750901273000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["IL-36\/IL-36R signaling promotes CD4+ T cell-dependent colitis via pro-inflammatory cytokine production"],"prefix":"10.3389","volume":"16","author":[{"given":"Maya","family":"Maarouf","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Kuczma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy L.","family":"Denning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2020.00517","article-title":"Personalizing treatment in IBD: hype or reality in 2020? 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