{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T19:58:40Z","timestamp":1792180720254,"version":"4.4.0"},"reference-count":61,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2022,8,10]],"date-time":"2022-08-10T00:00:00Z","timestamp":1660089600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Medical Research Council (NMRC)"},{"name":"Goh Foundation"},{"name":"NMRC\/OFYIRG\/0053\/2017"},{"name":"AME YIRG award A2084c0157"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Interleukin 11 (IL11) is upregulated in inflammatory conditions, where it is mostly believed to have anti-inflammatory activity. However, recent studies suggest instead that IL11 promotes inflammation by activating fibroblasts. Here, we assessed whether IL11 is pro- or anti-inflammatory in fibroblasts. Primary cultures of human kidney, lung or skin fibroblasts were stimulated with IL11 that resulted in the transient phosphorylation of signal transducer and activator of transcription 3 (STAT3) and the sustained activation of extracellular signal-regulated protein kinases (ERK). RNA sequencing over a time course of IL11 stimulation revealed a robust but short-lived transcriptional response that was enriched for gene set hallmarks of inflammation and characterized by the upregulation of SERPINB2, TNFRSF18, Interleukin 33 (IL33), CCL20, IL1RL1, CXCL3\/5\/8, ICAM1 and IL11 itself. IL33 was the most upregulated signaling factor (38-fold, p = 9.8 \u00d7 10\u22125), and IL1RL1, its cognate receptor, was similarly increased (18-fold, p = 1.1 \u00d7 10\u221234). In proteomic studies, IL11 triggered a proinflammatory secretome with the notable upregulation of IL8, IL6, MCP1, CCL20 and CXCL1\/5\/6, which are important chemotaxins for neutrophils, monocytes, and lymphocytes. IL11 induced IL33 expression across fibroblast types, and the inhibition of STAT3 but not of MEK\/ERK prevented this. These data establish IL11 as pro-inflammatory with specific importance for priming the IL33 alarmin response in inflammatory fibroblasts across tissues.<\/jats:p>","DOI":"10.3390\/ijms23168900","type":"journal-article","created":{"date-parts":[[2022,8,10]],"date-time":"2022-08-10T09:42:56Z","timestamp":1660124576000},"page":"8900","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":66,"title":["IL11 Stimulates IL33 Expression and Proinflammatory Fibroblast Activation across Tissues"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9404-7608","authenticated-orcid":false,"given":"Anissa A.","family":"Widjaja","sequence":"first","affiliation":[{"name":"Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Chothani","sequence":"additional","affiliation":[{"name":"Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9263-1656","authenticated-orcid":false,"given":"Sivakumar","family":"Viswanathan","sequence":"additional","affiliation":[{"name":"Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9313-4195","authenticated-orcid":false,"given":"Joyce Wei Ting","family":"Goh","sequence":"additional","affiliation":[{"name":"Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0311-943X","authenticated-orcid":false,"given":"Wei-Wen","family":"Lim","sequence":"additional","affiliation":[{"name":"Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore"},{"name":"National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore 169609, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart A.","family":"Cook","sequence":"additional","affiliation":[{"name":"Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore"},{"name":"National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore 169609, Singapore"},{"name":"MRC-London Institute of Medical Sciences, Hammersmith Hospital Campus, London SW7 2AZ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7512","DOI":"10.1073\/pnas.87.19.7512","article-title":"Molecular Cloning of a cDNA Encoding Interleukin 11, a Stromal Cell-Derived Lymphopoietic and Hematopoietic Cytokine","volume":"87","author":"Paul","year":"1990","journal-title":"Proc. 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