{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:12:51Z","timestamp":1753891971752,"version":"3.41.2"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,7]],"date-time":"2022-03-07T00:00:00Z","timestamp":1646611200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Cytokine release syndrome (CRS) is one of the leading causes of morbidity and mortality in COVID-19 patients with elevated levels of circulating cytokines contributing to various clinical symptoms. Favorable control of CRS represents a promising and effective strategy to mitigate the clinical outcomes of hospitalized patients with moderate to severe pneumonia. Using<jats:italic>in vivo<\/jats:italic>cytokine release assay in human peripheral blood mononuclear cell (PBMC)-engrafted immunodeficient mice, we reported that 17\u03b1-hydroxyprogesterone caproate (17-OHPC), a synthetic progestogen, exhibited significant inhibition of OKT-3-stimulated production of numerous cytokines including TNF-\u03b1, IFN-\u03b3, IL-2, IL-4, IL-6, IL-10, and GM-CSF. Furthermore, 17-OHPC inhibited<jats:italic>in vitro<\/jats:italic>production of IFN-\u03b3, IL-1\u03b2, IL-2, IL-6, and IL-10 in human PBMCs stimulated with OKT3, while exhibiting down-regulation of the mRNA levels of TNF-\u03b1, IFN-\u03b3, IL-2, IL-6, and IL-10. Using the same human PBMCs, additional stimulators anti-CD28 antibody or PHA treatments led to substantial cytokine production, which was also attenuated by 17-OHPC. OKT3-stimulated phosphorylation of I\u03baB\u03b1 and nuclear translocation of NF-\u03baB p65 in human PBMCs were also reversed by 17-OHPC, suggesting its inhibition on NF-\u03baB signaling in immune cells. Taken together, this work reported both<jats:italic>in vivo<\/jats:italic>and<jats:italic>in vitro<\/jats:italic>inhibition of cytokine production by 17-OHPC, presumably by virtue of its suppression of NF-\u03baB signaling. These findings provide pharmacological evidence to support the potential application of 17-OHPC in treating CRS associated with COVID-19.<\/jats:p>","DOI":"10.3389\/fphar.2022.831315","type":"journal-article","created":{"date-parts":[[2022,3,7]],"date-time":"2022-03-07T08:51:55Z","timestamp":1646643115000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["17\u03b1-Hydroxyprogesterone Caproate Inhibits Cytokine Production via Suppression of NF-\u03baB Activation"],"prefix":"10.3389","volume":"13","author":[{"given":"Tao","family":"Hu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chengjifu","family":"Tang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sydney","family":"Stern","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tom","family":"Du","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,3,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"807","DOI":"10.3390\/ph14080807","article-title":"Lung Fibrosis after COVID-19: Treatment Prospects","volume":"14","author":"Bazdyrev","year":"2021","journal-title":"Pharmaceuticals (Basel)"},{"key":"B2","doi-asserted-by":"publisher","first-page":"iv91","DOI":"10.1136\/ard.2005.042564","article-title":"Superagonistic Anti-CD28 Antibodies: Potent Activators of Regulatory T Cells for the Therapy of Autoimmune Diseases","volume":"64","author":"Beyersdorf","year":"2005","journal-title":"Ann. 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