{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T23:55:52Z","timestamp":1783122952045,"version":"3.54.6"},"reference-count":43,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T00:00:00Z","timestamp":1655856000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004564","name":"Ministry of Education, Science and Technological Development of the Republic of Serbia","doi-asserted-by":"publisher","award":["451-03-68\/2022-14\/200015"],"award-info":[{"award-number":["451-03-68\/2022-14\/200015"]}],"id":[{"id":"10.13039\/501100004564","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The calcium-binding proteins S100A4, S100A8, and S100A9 are upregulated in chronic lymphocytic leukemia (CLL), while the S100A9 promotes NF-\u03baB activity during disease progression. The S100-protein family has been involved in several malignancies as mediators of inflammation and proliferation. The hypothesis of our study is that S100A proteins are mediators in signaling pathways associated with inflammation-induced proliferation, such as NF-\u03baB, PI3K\/AKT, and JAK\/STAT. The mononuclear cells (MNCs) of CLL were treated with proinflammatory IL-6, anti-inflammatory IL-10 cytokines, inhibitors of JAK1\/2, NF-\u03baB, and PI3K signaling pathways, to evaluate S100A4, S100A8, S100A9, and S100A12 expression as well as NF-\u03baB activation by qRT-PCR, immunocytochemistry, and immunoblotting. The quantity of S100A4, S100A8, and S100A9 positive cells (p &lt; 0.05) and their protein expression (p &lt; 0.01) were significantly decreased in MNCs of CLL patients compared to healthy controls. The S100A levels were generally increased in CD19+ cells compared to MNCs of CLL. The S100A4 gene expression was significantly stimulated (p &lt; 0.05) by the inhibition of the PI3K\/AKT signaling pathway in MNCs. IL-6 stimulated S100A4 and S100A8 protein expression, prevented by the NF-\u03baB and JAK1\/2 inhibitors. In contrast, IL-10 reduced S100A8, S100A9, and S100A12 protein expressions in MNCs of CLL. Moreover, IL-10 inhibited activation of NF-\u03baB signaling (4-fold, p &lt; 0.05). In conclusion, inflammation stimulated the S100A protein expression mediated via the proliferation-related signaling and balanced by the cytokines in CLL.<\/jats:p>","DOI":"10.3390\/ijms23136952","type":"journal-article","created":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T21:31:06Z","timestamp":1655933466000},"page":"6952","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Regulation of S100As Expression by Inflammatory Cytokines in Chronic Lymphocytic Leukemia"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3977-2780","authenticated-orcid":false,"given":"Olivera","family":"Mitrovi\u0107 Ajti\u0107","sequence":"first","affiliation":[{"name":"Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, 11129 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5132-8319","authenticated-orcid":false,"given":"Tijana","family":"Suboti\u010dki","sequence":"additional","affiliation":[{"name":"Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, 11129 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milo\u0161","family":"Dikli\u0107","sequence":"additional","affiliation":[{"name":"Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, 11129 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dragoslava","family":"\u0110iki\u0107","sequence":"additional","affiliation":[{"name":"Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, 11129 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0232-5322","authenticated-orcid":false,"given":"Milica","family":"Vukoti\u0107","sequence":"additional","affiliation":[{"name":"Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, 11129 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teodora","family":"Dragojevi\u0107","sequence":"additional","affiliation":[{"name":"Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, 11129 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilija","family":"\u017divkovi\u0107","sequence":"additional","affiliation":[{"name":"Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, 11129 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darko","family":"Anti\u0107","sequence":"additional","affiliation":[{"name":"Lymphoma Center, Clinic for Hematology, University Clinical Center of Serbia, 11000 Belgrade, Serbia"},{"name":"Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0362-1449","authenticated-orcid":false,"given":"Vladan","family":"\u010coki\u0107","sequence":"additional","affiliation":[{"name":"Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, 11129 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"32031","DOI":"10.18632\/oncotarget.8672","article-title":"STAT3 and NF-kappaB cooperatively control in vitro spontaneous apoptosis and poor chemo-responsiveness in patients with chronic lymphocytic leukemia","volume":"7","author":"Liu","year":"2016","journal-title":"Oncotarget"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1158\/1541-7786.MCR-10-0559","article-title":"STAT-3 Activates NF-kB in Chronic Lymphocytic Leukemia Cells","volume":"9","author":"Liu","year":"2011","journal-title":"Mol. 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