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Current interleukin-6-targeted therapies block both pathways, thereby disrupting essential homeostatic functions initiated by classic signalling. We here show a high-affinity, human-specific antibody that selectively inhibits interleukin-6 trans-signalling. This antibody maintains classic signalling-induced expression of hepatic acute phase genes while completely blocking trans-signalling-induced activation of endothelial cells. By targeting the domain D2 of membrane-bound and soluble human interleukin-6 receptor, the antibody selectively prevents formation of the trans-signalling receptor complex without interfering with ligand binding. This selective blockade demonstrates that human interleukin-6 classic and trans-signalling proceed through distinct receptor assemblies. Our findings describe mechanistic insight into interleukin-6 receptor assembly and provide a strategy to suppress inflammatory interleukin-6 activity while preserving regenerative and anti-inflammatory signalling, thus offering both conceptual and potential therapeutic advances in the targeted modulation of cytokine signalling networks.<\/jats:p>","DOI":"10.1038\/s42003-026-11014-0","type":"journal-article","created":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T21:56:54Z","timestamp":1792015014000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Selective inhibition of IL-6 trans-signalling reveals distinct mechanisms of human classic and trans-signalling receptor-complex formation"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-6662-0450","authenticated-orcid":false,"given":"Emelie","family":"Rieneck","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan Ren\u00e9","family":"Haak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamal","family":"Asgarov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Ren\u00e9","family":"Pallandre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0894-8448","authenticated-orcid":false,"given":"Nicole","family":"Wundrack","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Ettich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6619-9524","authenticated-orcid":false,"given":"Niloufarsadat","family":"Miri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6675-5313","authenticated-orcid":false,"given":"Doreen M.","family":"Floss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9932-1055","authenticated-orcid":false,"given":"J\u00fcrgen","family":"Scheller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4939-6950","authenticated-orcid":false,"given":"Christoph","family":"Garbers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andy","family":"Clark","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Wijdenes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8899-5414","authenticated-orcid":false,"given":"Fred","family":"Schaper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1056-4219","authenticated-orcid":false,"given":"Anna","family":"Dittrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,14]]},"reference":[{"key":"11014_CR1","doi-asserted-by":"crossref","unstructured":"Rose-John, S., Jenkins, B. 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