{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T02:14:29Z","timestamp":1775182469949,"version":"3.50.1"},"reference-count":58,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T00:00:00Z","timestamp":1762732800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Uehara Memorial Foundation Research Fellowship"},{"name":"International Medical Research Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Differentiation of oligodendrocytes and myelination are enhanced by interleukin-4, an anti-inflammatory cytokine secreted from immune cells or injured neurons, and peroxisome proliferator-activated receptor \u03b3 serves as a central effector. While intracellular zinc concentrations have recently been reported to change dynamically during oligodendrocyte development, the role of zinc in interleukin-4-enhanced oligodendrocyte differentiation has not been studied. Using primary oligodendroglial cells and the oligodendroglial CG4 cell line, we show that intracellular zinc concentrations transiently increased 1 day after interleukin-4-induced differentiation and that intracellular as well as extracellular zinc chelators repressed the interleukin-4-dependent effects. Our analyses furthermore reveal that STAT6 activated the zinc transporter ZIP11 downstream of interleukin-4 in a phosphorylation-dependent manner and that siRNA-dependent knockdown of ZIP11 abolished the interleukin-4-enhanced oligodendrocyte differentiation. An antagonist of peroxisome proliferator-activated receptor \u03b3 similarly repressed the interleukin-4-dependent differentiation. However, agonists did not affect intracellular zinc concentrations. These findings indicate that interleukin-4 upregulates ZIP11 expression via activation of STAT6 and facilitates extracellular zinc uptake, which in turn activates peroxisome proliferator-activated receptor \u03b3 and thereby promotes oligodendrocytes differentiation. Our results argue that a modulation of zinc concentrations may be beneficial for promoting oligodendrocyte differentiation and remyelination under demyelinating conditions such as multiple sclerosis.<\/jats:p>","DOI":"10.3390\/cells14221756","type":"journal-article","created":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T11:47:27Z","timestamp":1762775247000},"page":"1756","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Interleukin-4-Enhanced Oligodendrocyte Differentiation Depends on Extracellular Zinc Uptake via ZIP11"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4697-0593","authenticated-orcid":false,"given":"Takaaki","family":"Aratake","sequence":"first","affiliation":[{"name":"Institut f\u00fcr Biochemie, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Serika","family":"Kurita","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Biochemie, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4586-3294","authenticated-orcid":false,"given":"Michael","family":"Wegner","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Biochemie, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1002\/dneu.22849","article-title":"Using the Lineage Determinants Olig2 and Sox10 to Explore Transcriptional Regulation of Oligodendrocyte Development","volume":"81","author":"Sock","year":"2021","journal-title":"Dev. 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