{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T16:44:19Z","timestamp":1789058659107,"version":"build-2803163510"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T00:00:00Z","timestamp":1755216000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82172295"],"award-info":[{"award-number":["82172295"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p><jats:italic>Schistosomiasis japonica<\/jats:italic>, a zoonotic parasitic disease, induces complex immune regulation during infection. The inflammatory responses and immunosuppressive mechanisms co-exist to maintain immune homeostasis in schistosomiasis. B7-H4 is a critical immune checkpoint molecule that modulates T cell activation and exerts immunosuppressive effects. Our previous investigations revealed that B7-H4 mRNA expression was elevated in mice infected with <jats:italic>Schistosoma japonicum<\/jats:italic>, with interleukin-10 (IL-10) demonstrating regulatory capacity to enhance B7-H4 expression in RAW264.7 macrophages. In this study, we further explore the mechanism underlying IL-10-mediated B7-H4 upregulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Western blot was performed to detect B7-H4 expression levels, both in mice infected with <jats:italic>Schistosoma japonicum<\/jats:italic> and in RAW264.7 cells stimulated with IL-10. RT-qPCR was performed to screen microRNAs (miR-140 et al.) in RAW264.7 cells stimulated with IL-10. Then dual-luciferase reporter assay was performed to confirm that miR-140 can directly bind to the 3\u2019UTR of B7-H4. miR-140 promoter activity in RAW264.7 cells was also detected via dual-luciferase reporter assays. In addition, ChIP was performed to confirm the binding of transcription factors and miR-140 promoter.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Notably, miR-140 was decreased in IL-10-treated microphages, accompanied by B7-H4 expression was upregulated. miR-140 can directly bind to the 3\u2019UTR of B7-H4 and then inhibit the expression of B7-H4 in RAW264.7 cells. Meanwhile, miR-140 mimics can also attenuate IL-10-induced B7-H4 expression in RAW264.7 cells. Then we found that IL-10 may inhibit miR-140 promoter activity in RAW264.7 cells through transcription factors that binding to the - 576\/- 94 bp region of the miR-140 promoter. Results by Western blot and ChIP further indicated that IL-10 could downregulate miR-140 promoter activity in a STAT5 dependence manner. After the sequence of STAT5 binding site within the - 456\/- 446 bp region of the miR-140 promoter was mutated, IL-10 failed to suppress the activity produced by mutant miR-140 promoter.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>In summary, IL-10 can inhibit miR-140 through STAT5, thereby upregulating the expression of B7-H4 in RAW264.7 cells. This study may suggest a new mechanism underlying IL-10-mediated B7-H4 upregulation in macrophages.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcimb.2025.1613297","type":"journal-article","created":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T05:29:42Z","timestamp":1755235782000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["IL-10\/STAT5 axis suppresses miR-140 to upregulate B7-H4 expression in RAW264.7 cells"],"prefix":"10.3389","volume":"15","author":[{"given":"Dandan","family":"Zhu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiliang","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuxin","family":"Ji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinong","family":"Duan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxi","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,8,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/j.pt.2013.12.009","article-title":"Cellular and chemokine-mediated regulation in schistosome-induced hepatic pathology","volume":"30","author":"Chuah","year":"2014","journal-title":"Trends Parasitol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1016\/j.canlet.2015.08.011","article-title":"NRF2\/miR-140 signaling confers radioprotection to human lung fibroblasts","volume":"369","author":"Duru","year":"2015","journal-title":"Cancer Lett."},{"key":"B3","doi-asserted-by":"publisher","first-page":"108648","DOI":"10.1016\/j.intimp.2022.108648","article-title":"Toxoplasma gondii promotes microRNA-34a to inhibit Foxp3 expression in adverse outcomes of pregnancy in mice","volume":"107","author":"Gao","year":"2022","journal-title":"Int. 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