{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T11:21:28Z","timestamp":1793964088841,"version":"4.8.0"},"reference-count":47,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2024,4,5]],"date-time":"2024-04-05T00:00:00Z","timestamp":1712275200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Denso CORPORATION"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>Coccomyxa subellipsoidea KJ (C-KJ) is a green alga with unique immunoregulatory characteristics. Here, we investigated the mechanism underlying the modification of T cell function by C-KJ components. The water-soluble extract of C-KJ was fractionated into protein (P) and sugar (S) fractions acidic (AS), basic (BS), and neutral (NS). These fractions were used for the treatment of peripheral blood mononuclear cells stimulated with toxic shock syndrome toxin-1. Transcriptome analysis revealed that both P and AS enhanced the expression of the genes encoding metallothionein (MT) family proteins, inflammatory factors, and T helper (Th) 17 cytokine and suppressed that of those encoding Th2 cytokines in stimulated T cells. The kinetics of MT1 and MT2A gene expression showed a transient increase in MT1 and maintenance of MT2A mRNA after T cell stimulation in the presence of AS. The kinetics of Th17-related cytokine secretion in the early period were comparable to those of MT2A mRNA. Furthermore, our findings revealed that static, a STAT-3 inhibitor, significantly suppressed MT2A gene expression. These findings suggest that the expression of MTs is involved in the immune regulatory function of C-KJ components, which is partially regulated by Th17 responses, and may help develop innovative immunoregulatory drugs or functional foods.<\/jats:p>","DOI":"10.3390\/microorganisms12040741","type":"journal-article","created":{"date-parts":[[2024,4,5]],"date-time":"2024-04-05T08:27:52Z","timestamp":1712305672000},"page":"741","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Coccomyxa subellipsoidea KJ Components Enhance the Expression of Metallothioneins and Th17 Cytokines during Human T Cell Activation"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1963-5140","authenticated-orcid":false,"given":"Toshiro","family":"Seki","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Isehara 259-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shino","family":"Ohshima","sequence":"additional","affiliation":[{"name":"Department of Molecular Life Science, Division of Basic Medical Science, Tokai University School of Medicine, Isehara 259-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoko","family":"Komatsu","sequence":"additional","affiliation":[{"name":"DENSO CORPORATION, Kariya 448-0029, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soga","family":"Yamada","sequence":"additional","affiliation":[{"name":"Department of Molecular Life Science, Division of Basic Medical Science, Tokai University School of Medicine, Isehara 259-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirofumi","family":"Kashiwagi","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Tokai University School of Medicine, Isehara 259-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumiko","family":"Goto","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Tokai University School of Medicine, Isehara 259-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Banri","family":"Tsuda","sequence":"additional","affiliation":[{"name":"Department of Palliative Medicine, Tokai University School of Medicine, Isehara 259-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiko","family":"Kanno","sequence":"additional","affiliation":[{"name":"DENSO CORPORATION, Kariya 448-0029, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Yasuda","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Isehara 259-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Kuno","sequence":"additional","affiliation":[{"name":"DENSO CORPORATION, Kariya 448-0029, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriko M","family":"Tsuji","sequence":"additional","affiliation":[{"name":"Division of Immune Homeostasis, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo 113-8602, Japan"},{"name":"Division of Microbiology, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo 113-8602, Japan"},{"name":"Department of Food Science, Jumonji University, Niiza 352-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2067-6708","authenticated-orcid":false,"given":"Takashi","family":"Shiina","sequence":"additional","affiliation":[{"name":"Department of Molecular Life Science, Division of Basic Medical Science, Tokai University School of Medicine, Isehara 259-1193, Japan"},{"name":"Institute of Advanced Biosciences, Tokai University, Hiratsuka 259-1207, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7417-1836","authenticated-orcid":false,"given":"Yoshie","family":"Kametani","sequence":"additional","affiliation":[{"name":"Department of Molecular Life Science, Division of Basic Medical Science, Tokai University School of Medicine, Isehara 259-1193, Japan"},{"name":"Institute of Advanced Biosciences, Tokai University, Hiratsuka 259-1207, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1002\/ptr.7348","article-title":"Immunomodulatory effects of polysaccharides from marine algae for treating cancer, infectious disease, and inflammation","volume":"36","author":"Hwang","year":"2022","journal-title":"Phytother. Res."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Xia, D., Qiu, W., Wang, X., and Liu, J. (2021). Recent Advancements and Future Perspectives of Microalgae-Derived Pharmaceuticals. Mar. Drugs, 19.","DOI":"10.3390\/md19120703"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Gao, C., Wang, Y., Shen, Y., Yan, D., He, X., Dai, J., and Wu, Q. (2014). Oil accumulation mechanisms of the oleaginous microalga Chlorella protothecoides revealed through its genome, transcriptomes, and proteomes. BMC Genom., 15.","DOI":"10.1186\/1471-2164-15-582"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1039\/c2ee23129h","article-title":"An extremely radioresistant green eukaryote for radionuclide bio-decontamination in the nuclear industry","volume":"6","author":"Rivasseau","year":"2013","journal-title":"Energy Environ. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Hayashi, K., Lee, J.B., Atsumi, K., Kanazashi, M., Shibayama, T., Okamoto, K., Kawahara, T., and Hayashi, T. (2019). In vitro and in vivo anti-herpes simplex virus activity of monogalactosyl diacylglyceride from Coccomyxa sp. KJ (IPOD FERM BP-22254), a green microalga. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0219305"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Weyh, C., Kruger, K., Peeling, P., and Castell, L. (2022). The Role of Minerals in the Optimal Functioning of the Immune System. Nutrients, 14.","DOI":"10.3390\/nu14030644"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Guo, Q., Shao, Q., Xu, W., Rui, L., Sumi, R., Eguchi, F., and Li, Z. (2017). Immunomodulatory and Anti-IBDV Activities of the Polysaccharide AEX from Coccomyxa gloeobotrydiformis. Mar. Drugs, 15.","DOI":"10.3390\/md15020036"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2523","DOI":"10.1159\/000495922","article-title":"Coccomyxa Gloeobotrydiformis Polysaccharide Inhibits Lipopolysaccharide-Induced Inflammation in RAW 264.7 Macrophages","volume":"51","author":"Dai","year":"2018","journal-title":"Cell Physiol. Biochem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1038\/s41423-019-0220-6","article-title":"Helper T cell differentiation","volume":"16","author":"Saravia","year":"2019","journal-title":"Cell Mol. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1002\/0471142735.im1412s109","article-title":"Toll-like receptors","volume":"109","author":"Takeda","year":"2015","journal-title":"Curr. Protoc. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1660","DOI":"10.1111\/all.13788","article-title":"Innate immunity in allergy","volume":"74","author":"Maeda","year":"2019","journal-title":"Allergy"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2130","DOI":"10.1111\/cas.13648","article-title":"Generation and application of human induced-stem cell memory T cells for adoptive immunotherapy","volume":"109","author":"Kondo","year":"2018","journal-title":"Cancer Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1111\/1348-0421.12982","article-title":"Coccomyxa sp. KJ extract affects the fate of T cells stimulated by toxic shock syndrome toxin-1, a superantigen secreted by Staphylococcus aureus","volume":"66","author":"Ohshima","year":"2022","journal-title":"Microbiol. Immunol."},{"key":"ref_14","first-page":"9","article-title":"The Effect of Coccomyxa sp. KJ on Physical and Mental Conditions and Immune Function in Healthy Adults-A Placebo-controlled, Randomized, Double-blind Clinical Trial","volume":"50","author":"Kanno","year":"2022","journal-title":"Jpn. Pharmacol. Therapeut"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"F1000","DOI":"10.12688\/f1000research.15500.1","article-title":"Cholesterol metabolism in innate and adaptive response","volume":"7","author":"Reboldi","year":"2018","journal-title":"F1000Res"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1016\/j.advnut.2023.05.013","article-title":"\u03b2-Sitosterol as a Promising Anticancer Agent for Chemoprevention and Chemotherapy: Mechanisms of Action and Future Prospects","volume":"14","author":"Wang","year":"2023","journal-title":"Adv. Nutr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1111\/jpy.13164","article-title":"Sterol Biosynthesis in Four Green Algae: A Bioinformatic Analysis of the Ergosterol Versus Phytosterol Decision Point","volume":"57","author":"Voshall","year":"2021","journal-title":"J. Phycol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1007\/s11357-011-9377-3","article-title":"Zinc: Dietary intake and impact of supplementation on immune function in elderly","volume":"35","author":"Mocchegiani","year":"2013","journal-title":"Age"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1146\/annurev-nutr-080508-141119","article-title":"Functional significance of zinc-related signaling pathways in immune cells","volume":"29","author":"Haase","year":"2009","journal-title":"Annu. Rev. Nutr."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"101541","DOI":"10.1016\/j.arr.2021.101541","article-title":"Rebalancing the unbalanced aged immune system\u2014A special focus on zinc","volume":"74","author":"Baarz","year":"2022","journal-title":"Aging Res. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"D258","DOI":"10.1093\/nar\/gkh036","article-title":"The Gene Ontology (GO) database and informatics resource","volume":"32","author":"Harris","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"D354","DOI":"10.1093\/nar\/gkj102","article-title":"From genomics to chemical genomics: New developments in KEGG","volume":"34","author":"Kanehisa","year":"2006","journal-title":"Nucleic Acids Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1002\/eji.201747151","article-title":"Metallothionein-1 suppresses rheumatoid arthritis pathogenesis by shifting the Th17\/Treg balance","volume":"48","author":"Sun","year":"2018","journal-title":"Eur. J. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1002\/eji.201646723","article-title":"IL-17 and IL-22 in immunity: Driving protection and pathology","volume":"47","author":"Eyerich","year":"2017","journal-title":"Eur. J. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2981","DOI":"10.1016\/j.bbagen.2013.01.018","article-title":"Edible blue-green algae reduce the production of pro-inflammatory cytokines by inhibiting NF-kappaB pathway in macrophages and splenocytes","volume":"1830","author":"Ku","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.biochi.2019.09.012","article-title":"Microalgal carotenoids and phytosterols regulate biochemical mechanisms involved in human health and disease prevention","volume":"167","author":"Mayer","year":"2019","journal-title":"Biochimie"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Ishiguro, S., Roth, M., Welti, R., Loyd, M., Thakkar, R., Phillips, M., Robben, N., Upreti, D., Nakashima, A., and Suzuki, K. (2022). A Water Extract from Chlorella sorokiniana Cell Walls Stimulates Growth of Bone Marrow Cells and Splenocytes. Nutrients, 14.","DOI":"10.3390\/nu14142901"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1864","DOI":"10.4049\/jimmunol.1600410","article-title":"Zinc Induces Dendritic Cell Tolerogenic Phenotype and Skews Regulatory T Cell-Th17 Balance","volume":"197","author":"George","year":"2016","journal-title":"J. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2880","DOI":"10.1038\/s41467-023-38588-1","article-title":"Impaired expression of metallothioneins contributes to allergen-induced inflammation in patients with atopic dermatitis","volume":"14","author":"Sirvent","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1089\/dna.2019.4729","article-title":"T Helper 9 Cells: A New Player in Immune-Related Diseases","volume":"38","author":"Chen","year":"2019","journal-title":"DNA Cell Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e2250075","DOI":"10.1002\/eji.202250075","article-title":"Interleukin-21 in autoimmune and inflammatory skin diseases","volume":"53","author":"Bodner","year":"2023","journal-title":"Eur. J. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1279837","DOI":"10.3389\/fimmu.2023.1279837","article-title":"Interactions between neutrophils and T-helper 17 cells","volume":"14","author":"Fan","year":"2023","journal-title":"Front. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1039\/c3mt00281k","article-title":"Determination of elemental distribution in green micro-algae using synchrotron radiation nano X-ray fluorescence (SR-nXRF) and electron microscopy techniques\u2014Subcellular localization and quantitative imaging of silver and cobalt uptake by Coccomyxa actinabiotis","volume":"6","author":"Leonardo","year":"2014","journal-title":"Metallomics"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"739918","DOI":"10.3389\/fimmu.2021.739918","article-title":"Metallothionein 1: A New Spotlight on Inflammatory Diseases","volume":"12","author":"Dai","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12011-017-1061-8","article-title":"Metallothionein: A Potential Link in the Regulation of Zinc in Nutritional Immunity","volume":"182","author":"Rahman","year":"2018","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Subramanian Vignesh, K., and Deepe, G.S. (2017). Metallothioneins: Emerging Modulators in Immunity and Infection. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18102197"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1523\/JNEUROSCI.0962-17.2017","article-title":"MT3-MMP Promotes Excitatory Synapse Formation by Promoting Nogo-66 Receptor Ectodomain Shedding","volume":"38","author":"Sanz","year":"2018","journal-title":"J. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1080\/15384101.2023.2205209","article-title":"Zinc promotes cell proliferation via regulating metal-regulatory transcription factor 1 expression and transcriptional activity in pulmonary arterial hypertension","volume":"22","author":"Chen","year":"2023","journal-title":"Cell Cycle"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.abb.2016.02.020","article-title":"Immunological orchestration of zinc homeostasis: The battle between host mechanisms and pathogen defenses","volume":"611","author":"Vignesh","year":"2016","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/s41392-023-01679-y","article-title":"Cellular zinc metabolism and zinc signaling: From biological functions to diseases and therapeutic targets","volume":"9","author":"Chen","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1016\/j.bbrc.2011.03.084","article-title":"Intracellular free zinc up-regulates IFN-gamma and T-bet essential for Th1 differentiation in Con-A stimulated HUT-78 cells","volume":"407","author":"Bao","year":"2011","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1038\/ni1373","article-title":"Toll-like receptor-mediated regulation of zinc homeostasis influences dendritic cell function","volume":"7","author":"Kitamura","year":"2006","journal-title":"Nat. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1046\/j.1523-1747.2000.00862.x","article-title":"Cutaneous metallothionein induction by ultraviolet B irradiation in interleukin-6 null mice","volume":"114","author":"Nishimura","year":"2000","journal-title":"J. Investig. Dermatol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Yin, X., Knecht, D.A., and Lynes, M.A. (2005). Metallothionein mediates leukocyte chemotaxis. BMC Immunol., 6.","DOI":"10.1186\/1471-2172-6-21"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1093\/intimm\/dxq017","article-title":"Zinc suppresses Th17 development via inhibition of STAT3 activation","volume":"22","author":"Kitabayashi","year":"2010","journal-title":"Int. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Bonaventura, P., Lamboux, A., Albar\u00e8de, F., and Miossec, P. (2016). A Feedback Loop between Inflammation and Zn Uptake. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0147146"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1111\/j.1365-3083.1994.tb03390.x","article-title":"Interactions between staphylococcal superantigens and human T-cell clones are predominantly but not exclusively governed by their T-cell receptor V beta usage","volume":"39","author":"Lundin","year":"1994","journal-title":"Scand J. Immunol."}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/12\/4\/741\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:23:54Z","timestamp":1760106234000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/12\/4\/741"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,5]]},"references-count":47,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2024,4]]}},"alternative-id":["microorganisms12040741"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms12040741","relation":{},"ISSN":["2076-2607"],"issn-type":[{"value":"2076-2607","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,5]]}}}