{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T17:42:06Z","timestamp":1792690926684,"version":"4.5.0"},"reference-count":51,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T00:00:00Z","timestamp":1792368000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"name":"College students\u2019 innovative entrepreneurial training plan program, Guangdong Medical University","award":["GDMUCX2024254"],"award-info":[{"award-number":["GDMUCX2024254"]}]},{"name":"National Natural Science Foundation of China","award":["32570697"],"award-info":[{"award-number":["32570697"]}]},{"name":"Guangdong Medical University undergraduate innovation and entrepreneurship education base project","award":["JDXM2024007, JDXM2024080, JDXM2024147, JDXM2024181"],"award-info":[{"award-number":["JDXM2024007, JDXM2024080, JDXM2024147, JDXM2024181"]}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Interferon &amp; Cytokine Research"],"abstract":"<jats:p>\n                    Interleukin-37 (IL-37) is an anti-inflammatory member of interleukin-1 family. Alternative splicing generates five isoforms (IL-37a\u2013e) with distinct exon compositions. IL-37a has recently attracted increasing attention because it uniquely retains exon 3. Exon 3 encodes an N-terminal nuclear localization sequence (NLS) that enables autonomous nuclear translocation and harbors an elastase cleavage site at L21\/R22. Elastase cleavage produces N-terminal IL-37a (NIL-37a) and mature IL-37a (mIL-37a). Full-length IL-37a and NIL-37a can exert IL-1R8-independent nuclear regulatory and anti-inflammatory effects in the endotoxemic shock model. Nuclear IL-37a recruits a WDR5\/MLL4\/C\/EBP\u03b2-associated complex to promote\n                    <jats:italic toggle=\"yes\">PPARG<\/jats:italic>\n                    transcription, thereby linking cytokine signaling with chromatin regulation and PPAR\u03b3-mediated inflammatory control. These findings highlight IL-37a as a mechanistically distinct isoform and illustrate how isoform-specific sequence composition, proteolytic processing, and subcellular localization can diversify cytokine functions. This review synthesizes available evidence regarding the molecular basis of IL-37a nuclear activity, compartmentalized signaling and receptor-independent epigenetic regulation, in the context of nuclear cytokine biology and immunometabolic control. Collectively, IL-37a is a mechanistically distinct isoform whose alternative splicing, proteolytic processing, and nuclear trafficking shape compartment-specific signaling. In LPS-induced endotoxic shock, nuclear IL-37a acts independently of IL-1R8 to upregulate PPAR\u03b3 through WDR5\/MLL4\/C\/EBP\u03b2-associated chromatin regulation; however, isoform-specific evidence requires further validation, particularly in humans.\n                  <\/jats:p>","DOI":"10.1177\/10799907261499951","type":"journal-article","created":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T17:11:41Z","timestamp":1792429901000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["IL-37a, an Anti-Inflammatory Molecule and a Nuclear Cytokine: Linking Alternative Splicing, Nuclear Trafficking, and Epigenetic Regulation of Inflammation"],"prefix":"10.1177","author":[{"given":"Zhi-Ya","family":"Wang","sequence":"first","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, School of Medical Technology, Guangdong Medical University, Dongguan, P.R. China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong-Qi","family":"Feng","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Guangdong Medical Univerity, Dongguan, P.R. China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-Xin","family":"Hu","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Guangdong Medical Univerity, Dongguan, P.R. China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan-Yu","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Guangdong Medical Univerity, Dongguan, P.R. China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Yun","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Guangdong Medical Univerity, Dongguan, P.R. China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sen","family":"Wang","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, School of Medical Technology, Guangdong Medical University, Dongguan, P.R. China."},{"name":"School of Basic Medical Sciences, Guangdong Medical Univerity, Dongguan, P.R. China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5141-5076","authenticated-orcid":false,"given":"Jian-Jun","family":"Xie","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, School of Medical Technology, Guangdong Medical University, Dongguan, P.R. China."},{"name":"School of Basic Medical Sciences, Guangdong Medical Univerity, Dongguan, P.R. China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,10,19]]},"reference":[{"key":"e_1_3_4_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2017.01.006"},{"key":"e_1_3_4_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.212519099"},{"key":"e_1_3_4_4_1","doi-asserted-by":"publisher","DOI":"10.1006\/geno.2000.6184"},{"key":"e_1_3_4_5_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.add1219"},{"key":"e_1_3_4_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1675791"},{"key":"e_1_3_4_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.prp.2024.155208"},{"key":"e_1_3_4_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kew325"},{"key":"e_1_3_4_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-024-01262-0"},{"key":"e_1_3_4_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellimm.2023.104759"},{"key":"e_1_3_4_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xjidi.2023.100205"},{"issue":"3","key":"e_1_3_4_12_1","first-page":"100","article-title":"IL-4, IL-1 receptor antagonist, IL-37, and IL-38 inhibit IL-1 and TNF generated by microglia","volume":"12","author":"Daliu P","year":"2023","unstructured":"Daliu P, , Scarano A. IL-4, IL-1 receptor antagonist, IL-37, and IL-38 inhibit IL-1 and TNF generated by microglia. Eur J Neurodegener Dis 2023;12(3):100\u2013103.","journal-title":"Eur J Neurodegener Dis"},{"key":"e_1_3_4_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni1110-973"},{"key":"e_1_3_4_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10930-026-10341-9"},{"key":"e_1_3_4_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13258-023-01455-w"},{"key":"e_1_3_4_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-025-01358-8"},{"key":"e_1_3_4_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2024.113787"},{"key":"e_1_3_4_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2023.06.191"},{"key":"e_1_3_4_19_1","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.052705"},{"key":"e_1_3_4_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2025.146357"},{"key":"e_1_3_4_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/nep.14381"},{"key":"e_1_3_4_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3153"},{"key":"e_1_3_4_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2024.02.030"},{"key":"e_1_3_4_24_1","doi-asserted-by":"publisher","DOI":"10.1006\/cyto.2002.0873"},{"key":"e_1_3_4_25_1","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2025.2604877"},{"key":"e_1_3_4_26_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.01503"},{"key":"e_1_3_4_27_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2023.1250216"},{"key":"e_1_3_4_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-022-00960-3"},{"key":"e_1_3_4_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2016.444"},{"key":"e_1_3_4_30_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms252312878"},{"key":"e_1_3_4_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41385-021-00477-5"},{"key":"e_1_3_4_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3103"},{"key":"e_1_3_4_33_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2026.1738156"},{"key":"e_1_3_4_34_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24119258"},{"key":"e_1_3_4_35_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.adn0327"},{"key":"e_1_3_4_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2022.12.019"},{"key":"e_1_3_4_37_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.2.1169"},{"key":"e_1_3_4_38_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2025.1653017"},{"key":"e_1_3_4_39_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.ade5728"},{"key":"e_1_3_4_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2026.05.006"},{"issue":"1","key":"e_1_3_4_41_1","first-page":"1","article-title":"IL-37 is an inhibitory cytokine that could be useful for treating infections","volume":"8","author":"Toniato E","year":"2024","unstructured":"Toniato E. IL-37 is an inhibitory cytokine that could be useful for treating infections. Int. J. Infect 2024;8(1):1\u20132.","journal-title":"Int. J. Infect"},{"key":"e_1_3_4_42_1","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/5498115"},{"key":"e_1_3_4_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.micpath.2023.106135"},{"key":"e_1_3_4_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2023.05.014"},{"key":"e_1_3_4_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-023-01091-0"},{"key":"e_1_3_4_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2025.113600"},{"key":"e_1_3_4_47_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-024-05180-0"},{"key":"e_1_3_4_48_1","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.1753"},{"key":"e_1_3_4_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2024.116268"},{"key":"e_1_3_4_50_1","doi-asserted-by":"publisher","DOI":"10.1111\/cns.14581"},{"key":"e_1_3_4_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-018-0664-0"},{"key":"e_1_3_4_52_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.ade4395"}],"container-title":["Journal of Interferon &amp; Cytokine Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/10799907261499951","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/10799907261499951","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/10799907261499951","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T17:18:22Z","timestamp":1792689502000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/10799907261499951"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,19]]},"references-count":51,"alternative-id":["10.1177\/10799907261499951"],"URL":"https:\/\/doi.org\/10.1177\/10799907261499951","relation":{},"ISSN":["1079-9907","1557-7465"],"issn-type":[{"value":"1079-9907","type":"print"},{"value":"1557-7465","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,19]]},"article-number":"10799907261499951"}}