{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:10:13Z","timestamp":1790208613740,"version":"4.1.0"},"reference-count":48,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2022,11,10]],"date-time":"2022-11-10T00:00:00Z","timestamp":1668038400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of Guangdong Province","award":["2021A1515011579"],"award-info":[{"award-number":["2021A1515011579"]}]},{"name":"National Natural Science Foundation of Guangdong Province","award":["GJHZ20190823111414825"],"award-info":[{"award-number":["GJHZ20190823111414825"]}]},{"name":"National Natural Science Foundation of Guangdong Province","award":["2021A05046"],"award-info":[{"award-number":["2021A05046"]}]},{"name":"Science and Technology Plan (International Cooperative Research) Project of Shenzhen","award":["2021A1515011579"],"award-info":[{"award-number":["2021A1515011579"]}]},{"name":"Science and Technology Plan (International Cooperative Research) Project of Shenzhen","award":["GJHZ20190823111414825"],"award-info":[{"award-number":["GJHZ20190823111414825"]}]},{"name":"Science and Technology Plan (International Cooperative Research) Project of Shenzhen","award":["2021A05046"],"award-info":[{"award-number":["2021A05046"]}]},{"name":"Science and Technology Project of Zhanjiang","award":["2021A1515011579"],"award-info":[{"award-number":["2021A1515011579"]}]},{"name":"Science and Technology Project of Zhanjiang","award":["GJHZ20190823111414825"],"award-info":[{"award-number":["GJHZ20190823111414825"]}]},{"name":"Science and Technology Project of Zhanjiang","award":["2021A05046"],"award-info":[{"award-number":["2021A05046"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Microglia activation, increased IL-6 and decreased TGF-\u03b2 were found in depressed patients or in animal models of depression. IL-6 enhances T helper 17 cell differentiation, thereby causing an imbalance between Th17 and Treg cells, which induces neuroinflammation and neuronal dysfunction. However, whether imbalances between IL-6 and TGF-\u03b2 and between Th17 and Treg occur in depression and whether depression can be improved upon restoring these imbalances are unknown. Treg promoter IL-2 (1500UI\/0.1 mL\/day) was used to treat a mouse model of depression induced by chronic unpredictable mild stress (CUMS). The behavior and concentrations of IL-6, TGF-\u03b2, Th17, IL-17A, IL-17Rc, Treg-related factors (helios and STAT5), astrocyte A1 phenotype S100\u03b2, microglia M1 phenotype Iba-1, indoleamine-2,3-dioxygenase (IDO) enzyme, corticosterone (CORT) and neurotransmitters were evaluated. When compared to controls, CUMS reduced sucrose preference, the number of entries into and the time spent in the open arms of the elevated plus maze and the exploration in the \u201copen field\u201d, while it increased the immobility time in tail suspension, which was ameliorated by IL-2 treatment. RoR\u03b1, S100\u03b2, IL-17A, IL-17Rc, IL-6, Iba-1, IDO enzyme and CORT concentrations were significantly increased, and Helios, FoxP3+, STAT5 and TGF-\u03b2 were significantly decreased by CUMS, which were significantly attenuated by IL-2 when compared to the CUMS group. The NE, DA and 5-HT contents and those of their metabolites were decreased by CUMS, which returned to control levels after IL-2 treatment. The study demonstrated that imbalances between IL-6 and TGF-\u03b2 and between Th17and Treg occurred in the hippocampus of the depression model. IL-2 attenuated depression- and anxiety-like behaviors and normalized the neurotransmitter concentration and the activity of the IDO enzyme, astrocytes and microglia through restoring both balances, but it did not decrease the CORT concentration.<\/jats:p>","DOI":"10.3390\/ijms232213856","type":"journal-article","created":{"date-parts":[[2022,11,10]],"date-time":"2022-11-10T19:16:23Z","timestamp":1668107783000},"page":"13856","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":67,"title":["Low-Dose IL-2 Attenuated Depression-like Behaviors and Pathological Changes through Restoring the Balances between IL-6 and TGF-\u03b2 and between Th17 and Treg in a Chronic Stress-Induced Mouse Model of Depression"],"prefix":"10.3390","volume":"23","author":[{"given":"Chengyi","family":"Huang","sequence":"first","affiliation":[{"name":"Research Institute for Marine Drugs and Nutrition, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524088, China"},{"name":"Marine Medicine and Development Center, Shenzhen Institute of Guangdong Ocean University, Shenzhen 518120, China"},{"name":"Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524088, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fucheng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Research Institute for Marine Drugs and Nutrition, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524088, China"},{"name":"Marine Medicine and Development Center, Shenzhen Institute of Guangdong Ocean University, Shenzhen 518120, China"},{"name":"Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524088, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1695-512X","authenticated-orcid":false,"given":"Peng","family":"Li","sequence":"additional","affiliation":[{"name":"Research Institute for Marine Drugs and Nutrition, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524088, China"},{"name":"Marine Medicine and Development Center, Shenzhen Institute of Guangdong Ocean University, Shenzhen 518120, China"},{"name":"Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524088, China"},{"name":"Affiliated Hospital of Guangdong Medical University, Zhanjiang 524088, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cai","family":"Song","sequence":"additional","affiliation":[{"name":"Research Institute for Marine Drugs and Nutrition, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524088, China"},{"name":"Marine Medicine and Development Center, Shenzhen Institute of Guangdong Ocean University, Shenzhen 518120, China"},{"name":"Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524088, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"104741","DOI":"10.1016\/j.yhbeh.2020.104741","article-title":"Hypothalamus-pituitary-adrenal axis imbalance and inflammation contribute to sex differences in separation- and restraint-induced depression","volume":"122","author":"Dong","year":"2020","journal-title":"Horm. Behav."},{"key":"ref_2","first-page":"7","article-title":"Depression: The case for a monoamine deficiency","volume":"61","author":"Delgado","year":"2000","journal-title":"J. Clin. Psychiatry"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.bbi.2021.01.016","article-title":"Elevated peripheral inflammation is associated with attenuated striatal reward anticipation in major depressive disorder","volume":"93","author":"Burrows","year":"2021","journal-title":"Brain Behav. Immun."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1016\/S0889-1591(02)00012-0","article-title":"The effect of thymectomy and IL-1 on memory: Implications for the relationship between immunity and depression","volume":"16","author":"Song","year":"2002","journal-title":"Brain Behav. Immun."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/7854_2016_37","article-title":"Immune-to-Brain Communication Pathways in Inflammation-Associated Sickness and Depression","volume":"31","author":"Mello","year":"2016","journal-title":"Curr. Top. Behav. Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1002\/glia.23143","article-title":"An astroglial basis of major depressive disorder? An overview","volume":"65","author":"Wang","year":"2017","journal-title":"Glia"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"6997","DOI":"10.1007\/s12035-015-9617-0","article-title":"Indoleamine-2, 3-Dioxygenase\/Kynurenine Pathway as a Potential Pharmacological Target to Treat Depression Associated with Diabetes","volume":"53","author":"Carabelli","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1038\/cmi.2015.89","article-title":"The regulation of the Treg\/Th17 balance by mesenchymal stem cells in human systemic lupus erythematosus","volume":"14","author":"Wang","year":"2017","journal-title":"Cell. Mol. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1038\/s41423-018-0186-9","article-title":"Upregulation of CD81 in trophoblasts induces an imbalance of Treg\/Th17 cells by promoting IL-6 expression in preeclampsia","volume":"16","author":"Ding","year":"2019","journal-title":"Cell. Mol. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1016\/j.it.2004.09.015","article-title":"The chemokine system in diverse forms of macrophage activation and polarization","volume":"25","author":"Mantovani","year":"2004","journal-title":"Trends Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"7119","DOI":"10.4049\/jimmunol.0802656","article-title":"TLR2 deficiency leads to increased Th17 infiltrates in experimental brain abscesses","volume":"182","author":"Nichols","year":"2009","journal-title":"J. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1007\/s00401-015-1402-7","article-title":"The role of IL-17 in CNS diseases","volume":"129","author":"Waisman","year":"2015","journal-title":"Acta Neuropathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1097\/WCO.0000000000000454","article-title":"Endothelial cells and lymphatics at the interface between the immune and central nervous systems: Implications for multiple sclerosis","volume":"30","author":"Liblau","year":"2017","journal-title":"Curr. Opin. Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1016\/S0306-4522(98)00271-1","article-title":"Variations of nucleus accumbens dopamine and serotonin following systemic interleukin-1, interleukin-2 or interleukin-6 treatment","volume":"88","author":"Song","year":"1999","journal-title":"Neuroscience"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/j.jpsychires.2021.06.033","article-title":"Faster speed of onset of the depressive episode is associated with lower cytokine serum levels (IL-2, -4, -6, -10, TNF-\u03b1 and IFN-\u03b3) in patients with major depression","volume":"141","author":"Fakhri","year":"2021","journal-title":"J. Psychiatr. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/0006-3223(89)90018-8","article-title":"Mitogen-stimulated lymphocyte proliferation and pituitary hormones in major depression","volume":"26","author":"Darko","year":"1989","journal-title":"Biol. Psychiatry"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1038\/ni1263","article-title":"A function for interleukin 2 in Foxp3-expressing regulatory T cells","volume":"6","author":"Fontenot","year":"2005","journal-title":"Nat. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5048","DOI":"10.7150\/thno.41534","article-title":"Low-dose interleukin-2 alleviates dextran sodium sulfate-induced colitis in mice by recovering intestinal integrity and inhibiting AKT-dependent pathways","volume":"10","author":"Lee","year":"2020","journal-title":"Theranostics"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e126294","DOI":"10.1172\/jci.insight.126294","article-title":"PP2A enables IL-2 signaling by preserving IL-2R\u03b2 chain expression during Treg development","volume":"5","author":"Sharabi","year":"2019","journal-title":"JCI Insight"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1159\/000097205","article-title":"Interleukin-2-induced changes in behavioural, neurotransmitter, and immunological parameters in the olfactory bulbectomized rat","volume":"2","author":"Song","year":"1995","journal-title":"Neuroimmunomodulation"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/0306-9877(91)90272-Z","article-title":"The macrophage theory of depression","volume":"35","author":"Smith","year":"1991","journal-title":"Med. Hypotheses"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1038\/nn.2139","article-title":"The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress","volume":"11","author":"Lutter","year":"2008","journal-title":"Nat. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1016\/S0006-3223(99)00234-6","article-title":"Alpha-1-noradrenergic neurotransmission, corticosterone, and behavioral depression","volume":"46","author":"Stone","year":"1999","journal-title":"Biol. Psychiatry"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1126\/science.aad0616","article-title":"Stable inhibitory activity of regulatory T cells requires the transcription factor Helios","volume":"350","author":"Kim","year":"2015","journal-title":"Science"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1016\/j.it.2020.07.006","article-title":"Microglia and Astrocytes in Disease: Dynamic Duo or Partners in Crime?","volume":"41","author":"Liddelow","year":"2020","journal-title":"Trends Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1821","DOI":"10.1002\/glia.23634","article-title":"Microglia responses to interleukin-6 and type I interferons in neuroinflammatory disease","volume":"67","author":"West","year":"2019","journal-title":"Glia"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.bbi.2019.08.185","article-title":"Increased IL-6 expression in astrocytes is associated with emotionality, alterations in central amygdala GABAergic transmission, and excitability during alcohol withdrawal","volume":"82","author":"Roberts","year":"2019","journal-title":"Brain Behav. Immun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"102313","DOI":"10.1016\/j.plefa.2021.102313","article-title":"Endogenous \u03c9-3 fatty acids in Fat-1 mice attenuated depression-like behaviors, spatial memory impairment and relevant changes induced by olfactory bulbectomy","volume":"171","author":"Gu","year":"2021","journal-title":"Prostaglandins Leukot. Essent. Fat. Acids"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s12974-019-1398-3","article-title":"Cathepsin C promotes microglia M1 polarization and aggravates neuroinflammation via activation of Ca-dependent PKC\/p38MAPK\/NF-\u03baB pathway","volume":"16","author":"Liu","year":"2019","journal-title":"J. Neuroinflammation"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"148112","DOI":"10.1016\/j.brainres.2022.148112","article-title":"Neuronal-Microglial Liver X receptor \u03b2 Activating Decrease Neuroinflammation and Chronic Stress-induced Depression-Related Behavior in Mice","volume":"7","author":"Li","year":"2022","journal-title":"Brain Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.neulet.2011.07.055","article-title":"Brain-derived neurotrophic factor (BDNF) infusion restored astrocytic plasticity in the hippocampus of a rat model of depression","volume":"503","author":"Ye","year":"2011","journal-title":"Neurosci. Lett."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"112296","DOI":"10.1016\/j.bbr.2019.112296","article-title":"SRT2104 attenuates chronic unpredictable mild stress-induced depressive-like behaviors and imbalance between microglial M1 and M2 phenotypes in the mice","volume":"378","author":"Duan","year":"2020","journal-title":"Behav. Brain Res."},{"key":"ref_33","first-page":"8065147","article-title":"Association of Pathogenic Th17 Cells with the Disease Severity and Its Potential Implication for Biological Treatment Selection in Psoriasis Patients","volume":"2020","author":"Aguilar","year":"2020","journal-title":"Mediators Inflamm."},{"key":"ref_34","first-page":"11","article-title":"S100B: Astrocyte specific protein","volume":"26","author":"Tateishi","year":"2006","journal-title":"Nihon Shinkei Seishin Yakurigaku Zasshi"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1007\/s00441-014-1958-x","article-title":"Proton receptor GPR68 expression in dendritic-cell-like S100\u03b2-positive cells of rat anterior pituitary gland: GPR68 induces interleukin-6 gene expression in extracellular acidification","volume":"358","author":"Horiguchi","year":"2014","journal-title":"Cell Tissue Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4785","DOI":"10.4049\/jimmunol.180.7.4785","article-title":"Isoform-specific inhibition of ROR alpha-mediated transcriptional activation by human FOXP3","volume":"180","author":"Du","year":"2008","journal-title":"J. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/S0168-9525(00)89000-9","article-title":"Jaks and Stats in signaling by the cytokine receptor superfamily","volume":"11","author":"Ihle","year":"1995","journal-title":"Trends Genet."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1038\/nature06878","article-title":"TGF-beta-induced Foxp3 inhibits T (H) 17 cell differentiation by antagonizing RORgammat function","volume":"453","author":"Zhou","year":"2008","journal-title":"Nature"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"125","DOI":"10.3389\/fimmu.2018.00125","article-title":"Critical Role of TGF-\u03b2 and IL-2 Receptor Signaling in Foxp3 Induction by an Inhibitor of DNA Methylation","volume":"9","author":"Freudenberg","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.intimp.2019.02.035","article-title":"The therapeutic potential of ginkgolide K in experimental autoimmune encephalomyelitis via peripheral immunomodulation","volume":"70","author":"Yu","year":"2019","journal-title":"Int. Immunopharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1038\/nri3823","article-title":"The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases","volume":"15","author":"Klatzmann","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1159\/000079415","article-title":"Influence of chronic interleukin-2 infusion and stressors on sickness behaviors and neurochemical change in mice","volume":"11","author":"Sudom","year":"2004","journal-title":"Neuroimmunomodulation"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"112172","DOI":"10.1016\/j.bbr.2019.112172","article-title":"Dietary of n-3 polyunsaturated fatty acids influence neurotransmitter systems of rats exposed to unpredictable chronic mild stress","volume":"376","author":"Yang","year":"2019","journal-title":"Behav. Brain Res."},{"key":"ref_44","first-page":"794","article-title":"Subcutaneous Compared with Intraperitoneal KetamineXylazine for Anesthesia of Mice","volume":"55","author":"Abraham","year":"2016","journal-title":"J. Am. Assoc. Lab. Anim. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1038\/s41398-020-0808-8","article-title":"Reduction of depression-like behavior in rat model induced by ShRNA targeting norepinephrine transporter in locus coeruleus","volume":"10","author":"Du","year":"2020","journal-title":"Transl. Psychiatry"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.pnpbp.2016.04.010","article-title":"Therapeutic effects of stress-programmed lymphocytes transferred to chronically stressed mice","volume":"70","author":"Scheinert","year":"2016","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Peng, Z., Zhang, C., Yan, L., Zhang, Y., Yang, Z., Wang, J., and Song, C. (2020). EPA is More Effective than DHA to Improve Depression-Like Behavior, Glia Cell Dysfunction and Hippcampal Apoptosis Signaling in a Chronic Stress-Induced Rat Model of Depression. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21051769"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1016\/j.bbr.2018.07.001","article-title":"Minocycline ameliorates depressive behaviors and neuro-immune dysfunction induced by chronic unpredictable mild stress in the rat","volume":"356","author":"Zhang","year":"2019","journal-title":"Behav. Brain Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/22\/13856\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:13:55Z","timestamp":1760145235000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/22\/13856"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,10]]},"references-count":48,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["ijms232213856"],"URL":"https:\/\/doi.org\/10.3390\/ijms232213856","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,10]]}}}