{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T04:17:10Z","timestamp":1791605830333,"version":"4.3.4"},"reference-count":86,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Thyroid hormone synthesis involves several key steps culminating in the organification of iodide into iodothyronines, thyroxine, and triiodothyronine. To date, there is no clear mechanistic evidence of extrathyroidal iodothyronine synthesis. Upon iodine (KI\/I2) loading, human neutrophils produced significant amounts of de novo iodothyronines as determined by diagnostic immunoassay and LCMS\/MS. Treatment of neutrophils with sodium iodide resulted in a lower hormone yield, which was enhanced following the addition of copper chloride to culture media. The appearance of thyroid hormones was observed only after induction of the oxidative burst with PMA. Synthesis of hormones was abolished by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, DPI. Essential components for iodothyronine synthesis included hydrogen peroxide, myeloperoxidase, and either serum or thyroglobulin serving as an iodination substrate. In a series of novel experiments, we show a serine protease requirement for liberation of thyroid hormones from reservoirs of iodinated proteins. Serine proteases, proteinase K, and neutrophil-derived elastase, but not cysteine protease cathepsin B, released thyroxine from in vitro iodinated or native thyroid-derived thyroglobulin, respectively. Our studies show that neutrophil-mediated iodothyronine synthesis is an extracellular, multi-step, enzymatic process initiated upon cellular activation, but is independent of neutrophil viability window. Overall, this report presents a series of cellular and enzymatic experiments demonstrating the induction of thyroid hormones by non-classical mechanisms that can potentially regulate localized levels of iodothyronines.<\/jats:p>","DOI":"10.3390\/biom16081081","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T15:05:42Z","timestamp":1784819142000},"page":"1081","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Human Neutrophils Produce De Novo Thyroid Hormones Mediated by the Induction of the Oxidative Burst"],"prefix":"10.3390","volume":"16","author":[{"given":"Mahmood Y.","family":"Bilal","sequence":"first","affiliation":[{"name":"Clinical Immunology Laboratory, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA"},{"name":"Center for Cancer Cell Biology, Immunology, and Infection, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9890-8946","authenticated-orcid":false,"given":"Umida","family":"Ganieva","sequence":"additional","affiliation":[{"name":"Clinical Immunology Laboratory, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA"},{"name":"Center for Cancer Cell Biology, Immunology, and Infection, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thanh","family":"Luu","sequence":"additional","affiliation":[{"name":"Center for Cancer Cell Biology, Immunology, and Infection, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA"},{"name":"Reproductive Medicine and Immunology, Obstetrics and Gynecology, Clinical Sciences Department, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8409-1645","authenticated-orcid":false,"given":"Joanne","family":"Kwak-Kim","sequence":"additional","affiliation":[{"name":"Center for Cancer Cell Biology, Immunology, and Infection, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA"},{"name":"Reproductive Medicine and Immunology, Obstetrics and Gynecology, Clinical Sciences Department, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1145-1814","authenticated-orcid":false,"given":"Svetlana","family":"Dambaeva","sequence":"additional","affiliation":[{"name":"Clinical Immunology Laboratory, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA"},{"name":"Center for Cancer Cell Biology, Immunology, and Infection, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"key":"ref_1","unstructured":"Boron, W.F., and Boulpaep, E.L. 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