{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T15:29:10Z","timestamp":1784042950656,"version":"3.55.0"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T00:00:00Z","timestamp":1770595200000},"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:p>Acute pancreatitis (AP) is driven by premature enzyme activation, pancreatic tissue injury, and dysregulated immune responses. IL-35 and IL-37 are key anti-inflammatory mediators whose dynamic regulation influences disease severity. Circulating IL-35 is typically upregulated in AP, functioning through STAT1\/STAT4 signalling to suppress effector T-cell proliferation, inhibit Th1\/Th17 differentiation, and promote expansion of regulatory T and B cells, thereby limiting pro-inflammatory cytokine release (e.g., TNF, IL-6, IL-17) and reducing local and systemic inflammation. In contrast, IL-37 is often downregulated early in AP, impairing its ability to suppress NF-\u03baB and MAPK signalling, restrain dendritic cell and macrophage activation, and reduce gasdermin D (GSDMD)-mediated pyroptosis. Experimental restoration of IL-37 diminishes neutrophil and macrophage infiltration, mitigates pancreatic necrosis, and modulates STAT signalling. The interplay of upregulated IL-35 with insufficient IL-37, within a broader cytokine network, emphasises a compensatory yet incomplete anti-inflammatory response. IL-38, although mechanistically promising, has not yet been characterised in human or animal AP models, and its clinical translation remains hypothetical. These insights suggest that clinical strategies\u2014such as recombinant IL-37 therapy, IL-35 modulators, or combination cytokine-targeted interventions\u2014may restore immune homeostasis and improve outcomes in AP.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1728737","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T07:36:31Z","timestamp":1770622591000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["IL-35, IL-37, and IL-38 in acute pancreatitis: proposed immunopathogenic mechanisms and therapeutic potential"],"prefix":"10.3389","volume":"17","author":[{"given":"Hailong","family":"Yan","sequence":"first","affiliation":[{"name":"Department of Emergency Surgery, Shaanxi Provincial People\u2019s Hospital","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingbo","family":"Dang","sequence":"additional","affiliation":[{"name":"Department of Emergency Surgery, Shaanxi Provincial People\u2019s Hospital","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gongliang","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Emergency Surgery, Shaanxi Provincial People\u2019s Hospital","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longyang","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Emergency Surgery, Shaanxi Provincial People\u2019s Hospital","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Emergency Surgery, Shaanxi Provincial People\u2019s Hospital","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shisan","family":"Bao","sequence":"additional","affiliation":[{"name":"Center for Evidence-based Medicine, Gansu University of Chinese Medicine","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiujuan","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Hematology, Shaanxi Provincial People\u2019s Hospital","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2021.09.043","article-title":"Global incidence of acute pancreatitis is increasing over time: A systematic review and meta-analysis","volume":"162","author":"Iannuzzi","year":"2022","journal-title":"Gastroenterology"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.20317","article-title":"Acute pancreatitis: A review","volume":"325","author":"Mederos","year":"2021","journal-title":"JAMA"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.5694\/mja14.01333","article-title":"Acute pancreatitis: update on management","volume":"202","author":"Nesvaderani","year":"2015","journal-title":"Med J Aust"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1279539","article-title":"Immune response mechanisms in acute and chronic pancreatitis: strategies for therapeutic intervention","volume":"14","author":"Glaubitz","year":"2023","journal-title":"Front Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3390\/cells12111495","article-title":"The emerging roles of the adaptive immune response in acute pancreatitis","volume":"12","author":"Stojanovic","year":"2023","journal-title":"Cells"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.5114\/aoms\/178183","article-title":"Interleukins: pathophysiological role in acute pancreatitis","volume":"20","author":"Rafaqat","year":"2024","journal-title":"Arch Med Sci"},{"key":"B7","volume-title":"Nobel Prize in Physiology or Medicine 2025: They Discovered How the Immune System Is Kept in Check","author":"Karl\u00e9n","year":"2025"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/nature06306","article-title":"The inhibitory cytokine il-35 contributes to regulatory T-cell function","volume":"450","author":"Collison","year":"2007","journal-title":"Nature"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1952","article-title":"Il-35-mediated induction of a potent regulatory T cell population","volume":"11","author":"Collison","year":"2010","journal-title":"Nat Immunol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1089\/jir.2021.0147","article-title":"Interleukin-35: structure, function and its impact on immune-related diseases","volume":"41","author":"Ye","year":"2021","journal-title":"J Interferon Cytokine Res"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1600446","article-title":"Il-35 decelerates the inflammatory process by regulating inflammatory cytokine secretion and M1\/M2 macrophage ratio in psoriasis","volume":"197","author":"Zhang","year":"2016","journal-title":"J Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keu528","article-title":"Immunoregulatory role of il-35 in T cells of patients with rheumatoid arthritis","volume":"54","author":"Nakano","year":"2015","journal-title":"Rheumatol (Oxford)"},{"key":"B13","doi-asserted-by":"publisher","first-page":"154076","DOI":"10.1016\/j.cyto.2017.06.003","article-title":"Il-35, as a newly proposed homeostasis-associated molecular pattern, plays three major functions including anti-inflammatory initiator, effector, and blocker in cardiovascular diseases","volume":"122","author":"Li","year":"2019","journal-title":"Cytokine"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2227","article-title":"The composition and signaling of the il-35 receptor are unconventional","volume":"13","author":"Collison","year":"2012","journal-title":"Nat Immunol"},{"key":"B15","article-title":"Association between serum interleukin-35 levels and severity of acute pancreatitis","volume":"8","author":"Zhang","year":"2015","journal-title":"Int J Clin Exp Med"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2020.108330","article-title":"Il-35 promotes microglial M2 polarization in a rat model of diabetic neuropathic pain","volume":"685","author":"Jiang","year":"2020","journal-title":"Arch Biochem Biophys"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v30.i8.817","article-title":"Autoimmune pancreatitis: cornerstones and future perspectives","volume":"30","author":"Gallo","year":"2024","journal-title":"World J Gastroenterol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1097\/MPA.0b013e3182142fd2","article-title":"International consensus diagnostic criteria for autoimmune pancreatitis: guidelines of the international association of pancreatology","volume":"40","author":"Shimosegawa","year":"2011","journal-title":"Pancreas"},{"key":"B19","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1007\/s00535-022-01891-7","article-title":"Current status of type 1 (Igg4-related) autoimmune pancreatitis","volume":"57","author":"Uchida","year":"2022","journal-title":"J Gastroenterol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1007\/s00535-006-1862-6","article-title":"Autoimmune pancreatitis: proposal of igg4-related sclerosing disease","volume":"41","author":"Kamisawa","year":"2006","journal-title":"J Gastroenterol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1007\/s00535-020-01689-5","article-title":"Interleukin-35 promotes the differentiation of regulatory T cells and suppresses th2 response in igg4-related type 1 autoimmune pancreatitis","volume":"55","author":"Ito","year":"2020","journal-title":"J Gastroenterol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-020-0500-7","article-title":"Igg4-related disease: an update on pathophysiology and implications for clinical care","volume":"16","author":"Perugino","year":"2020","journal-title":"Nat Rev Rheumatol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1007\/s10238-024-01303-5","article-title":"Immunomodulatory effects of itr35 cell subpopulation and its research progress","volume":"24","author":"Yang","year":"2024","journal-title":"Clin Exp Med"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2011-300771","article-title":"Tumour necrosis factor alpha secretion induces protease activation and acinar cell necrosis in acute experimental pancreatitis in mice","volume":"62","author":"Sendler","year":"2013","journal-title":"Gut"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V75.5.1037.1037","article-title":"Structure and function of the leukocyte adhesion molecules cd11\/cd18","volume":"75","author":"Arnaout","year":"1990","journal-title":"Blood"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.add0665","article-title":"Neutrophils and macrophages drive tnf-induced lethality via trif\/cd14-mediated responses","volume":"7","author":"Muendlein","year":"2022","journal-title":"Sci Immunol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1642116","article-title":"Dichotomous roles of il-36 and il-38 in cardiovascular disease","volume":"16","author":"Zhang","year":"2025","journal-title":"Front Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1278521","article-title":"Novel insights into il-37: an anti-inflammatory cytokine with emerging roles in anti-cancer process","volume":"14","author":"Gu","year":"2023","journal-title":"Front Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1007\/s11426-023-1891","article-title":"Interleukin-37 protects against acinar cell pyroptosis in acute pancreatitis","volume":"7","author":"Ma","year":"2022","journal-title":"JCI Insight"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2013.07.157","article-title":"Age-related inflammatory mediators in coronary artery disease (Ii)","volume":"168","author":"Fang","year":"2013","journal-title":"Int J Cardiol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.2147\/OTT.S336548","article-title":"M2-type macrophages induce tregs generation by activating the tgf-beta\/smad signalling pathway to promote colorectal cancer development","volume":"14","author":"Ma","year":"2021","journal-title":"Onco Targets Ther"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.1051282","article-title":"The role of il-35 and il-37 in breast cancer - potential therapeutic targets for precision medicine","volume":"12","author":"Ma","year":"2022","journal-title":"Front Oncol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1186\/s12974-024-03295-1","article-title":"Il-37 suppresses cns autoimmunity by increasing the frequency of treg cells and reducing cd4 + T cell-derived il-10 production","volume":"21","author":"Yazdani","year":"2024","journal-title":"J Neuroinflamm"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1093\/qjmed\/hcab011","article-title":"Il-37-a putative therapeutic agent in cardiovascular diseases","volume":"115","author":"McCurdy","year":"2022","journal-title":"QJM"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1564357","article-title":"The distinct roles of il-37 and il-38 in non-small cell lung carcinoma and their clinical implications","volume":"16","author":"Zhang","year":"2025","journal-title":"Front Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.18502\/ijaai.v21i1.8609","article-title":"Evaluating the microrna expression of il-35 and il-37 in helicobacter pylori-infected patients with gastritis and gastric ulcer","volume":"21","author":"Ahmadnia","year":"2022","journal-title":"Iran J Allergy Asthma Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/136329","article-title":"The possible role of the novel cytokines il-35 and il-37 in inflammatory bowel disease","volume":"2014","author":"Li","year":"2014","journal-title":"Mediators Inflammation"},{"key":"B38","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1177\/20503121251380131","article-title":"Unravelling key genes and molecular pathways in gastric inflammation-tocancer transition through causal discovery: implications for early diagnosis and therapy","volume":"13","author":"Ren","year":"2025","journal-title":"SAGE Open Med"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3984","article-title":"Computational correction of copy number effect improves specificity of crispr-cas9 essentiality screens in cancer cells","volume":"49","author":"Meyers","year":"2017","journal-title":"Nat Genet"},{"key":"B40","doi-asserted-by":"publisher","first-page":"4851","DOI":"10.1038\/s41467-022-32570-z","article-title":"Predicting response to immunotherapy in gastric cancer via multi-dimensional analyses of the tumour immune microenvironment","volume":"13","author":"Chen","year":"2022","journal-title":"Nat Commun"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1728737\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T09:59:59Z","timestamp":1771927199000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1728737\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,9]]},"references-count":40,"alternative-id":["10.3389\/fimmu.2026.1728737"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1728737","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,9]]},"article-number":"1728737"}}