{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:37:47Z","timestamp":1787027867092,"version":"build-2736575974"},"reference-count":48,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,2,20]],"date-time":"2023-02-20T00:00:00Z","timestamp":1676851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Nature Science Foundation of China","doi-asserted-by":"publisher","award":["31772604"],"award-info":[{"award-number":["31772604"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Nature Science Foundation of China","doi-asserted-by":"publisher","award":["32272876"],"award-info":[{"award-number":["32272876"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Granulosa cells (GCs) are essential for follicular growth, oocyte maturation, and steroidogenesis in the ovaries. Interleukin (IL)-11 is known to play a crucial role in the decidualization of the uterus, however, the expression of the IL-11 system (IL-11, IL-11R\u03b1, and gp130) in the bovine ovary and its exact role in GCs have not been extensively studied. In this study, we identified the IL-11 signaling receptor complex in the bovine ovary and investigated the regulatory effects and underlying mechanism of IL-11R\u03b1 on the proliferation and steroidogenesis of GCs. We observed that the IL-11 complex was highly expressed in the GCs of large follicles. IL-11R\u03b1 knockdown significantly inhibited GC proliferation by inducing cell cycle arrest at the G1 phase, along with a significant downregulation of proliferating cell nuclear antigen (PCNA) and Cyclin D1 (CCND1) protein, and induced GC apoptosis by significantly upregulating the ratio of BCL-2-associated X protein (BAX) and B-cell lymphoma-2 (BCL-2). In addition, IL-11R\u03b1 knockdown attenuated the Janus kinase (JAK) 1\u2013signal transducer and activator of transcription 3 (STAT3) signaling, which is related to cell proliferation and apoptosis. Furthermore, the enzyme-linked immunosorbent assay (ELISA) indicated that IL-11R\u03b1 silencing decreased the basal and forskolin (FSK)-stimulated secretions of estradiol and progesterone in GC culture medium concomitantly with a remarkable decrease in cytochrome P450 family 19 subfamily A member 1 (CYP19A1) and steroidogenic acute regulatory protein (StAR). We subsequently determined that this reduction in steroidogenesis was in parallel with the decrease in phosphorylations of protein kinase A (PKA) substrates, cAMP-response element binding protein (CREB), extracellular regulated protein kinase (ERK) 1\/2, and p38 mitogen-activated protein kinase (MAPK). Taken together, these data indicate that the effects of IL-11\/IL-11R\u03b1 on the proliferation and steroidogenesis in bovine GCs is mediated by the JAK1-STAT3, PKA-CREB, p38MAPK, and ERK1\/2 signaling pathways. Our findings provide important insights into the local action of the IL-11 system in regulating ovarian function.<\/jats:p>","DOI":"10.3390\/cells12040673","type":"journal-article","created":{"date-parts":[[2023,2,21]],"date-time":"2023-02-21T02:30:35Z","timestamp":1676946635000},"page":"673","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Effects of IL-11\/IL-11 Receptor Alpha on Proliferation and Steroidogenesis in Ovarian Granulosa Cells of Dairy Cows"],"prefix":"10.3390","volume":"12","author":[{"given":"Hanxiao","family":"Wu","sequence":"first","affiliation":[{"name":"Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peihao","family":"Sun","sequence":"additional","affiliation":[{"name":"Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ce","family":"Lv","sequence":"additional","affiliation":[{"name":"Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinzhe","family":"Zhao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingxiao","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qunli","family":"Zhou","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Northwest A&F University, Xianyang 712100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaomei","family":"Tang","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Northwest A&F University, Xianyang 712100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1389-4640","authenticated-orcid":false,"given":"Liguo","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China"},{"name":"National Center for International Research on Animal Genetics, Breeding and Reproduction, Huazhong Agricultural University, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aixin","family":"Liang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China"},{"name":"National Center for International Research on Animal Genetics, Breeding and Reproduction, Huazhong Agricultural University, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1016\/S0015-0282(16)55079-1","article-title":"Detection of interleukin-6 in human follicular fluid","volume":"57","author":"Buyalos","year":"1992","journal-title":"Fertil. Steril."},{"key":"ref_2","first-page":"1750","article-title":"Interleukin-6: Effects on and production by rat granulosa cells in vitro","volume":"130","author":"Gorospe","year":"1992","journal-title":"Endocrinology"},{"key":"ref_3","first-page":"633","article-title":"Interleukin-6 biosynthesis in human preovulatory follicles: Some of its potential roles at ovulation","volume":"79","author":"Machelon","year":"1994","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s102380300012","article-title":"The clinical role of interleukin-6 and interleukin-6 soluble receptor in human follicular fluids","volume":"3","author":"Kawasaki","year":"2003","journal-title":"Clin. Exp. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1159\/000484885","article-title":"IL-6 Promotes FSH-Induced VEGF Expression Through JAK\/STAT3 Signaling Pathway in Bovine Granulosa Cells","volume":"44","author":"Yang","year":"2017","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4125","DOI":"10.1182\/blood.V84.12.4125.bloodjournal84124125","article-title":"Regulation of interleukin-11 protein and mRNA expression in neonatal and adult fibroblasts and endothelial cells","volume":"84","author":"Suen","year":"1994","journal-title":"Blood"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"10304","DOI":"10.1074\/jbc.M312757200","article-title":"Functional expression of the interleukin-11 receptor alpha-chain and evidence of antiapoptotic effects in human colonic epithelial cells","volume":"279","author":"Kiessling","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"7512","DOI":"10.1073\/pnas.87.19.7512","article-title":"Molecular cloning of a cDNA encoding interleukin 11, a stromal cell-derived lymphopoietic and hematopoietic cytokine","volume":"87","author":"Paul","year":"1990","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1038\/nm0398-303","article-title":"Infertility in female mice lacking the receptor for interleukin 11 is due to a defective uterine response to implantation","volume":"4","author":"Robb","year":"1998","journal-title":"Nat. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1189\/jlb.0410226","article-title":"More than a sidekick: The IL-6 family cytokine IL-11 links inflammation to cancer","volume":"88","author":"Putoczki","year":"2010","journal-title":"J. Leukoc. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1177\/1933719112450330","article-title":"Innate immunity, decidual cells, and preeclampsia","volume":"20","author":"Yeh","year":"2013","journal-title":"Reprod. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"36197","DOI":"10.1074\/jbc.M004648200","article-title":"Interleukin-11 signals through the formation of a hexameric receptor complex","volume":"275","author":"Barton","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1042\/bj3340297","article-title":"Interleukin-6-type cytokine signalling through the gp130\/Jak\/STAT pathway","volume":"334","author":"Heinrich","year":"1998","journal-title":"Biochem. J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.cytogfr.2012.04.001","article-title":"Plasticity and cross-talk of interleukin 6-type cytokines","volume":"23","author":"Garbers","year":"2012","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/j.str.2007.02.006","article-title":"The dynamics of signal triggering in a gp130-receptor complex","volume":"15","author":"Matadeen","year":"2007","journal-title":"Structure"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.ccr.2009.01.002","article-title":"gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis","volume":"15","author":"Bollrath","year":"2009","journal-title":"Cancer Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1053\/j.gastro.2010.06.057","article-title":"Interleukin-11 reduces TLR4-induced colitis in TLR2-deficient mice and restores intestinal STAT3 signaling","volume":"139","author":"Gibson","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.1038\/s41467-021-22450-3","article-title":"Interleukin-11-expressing fibroblasts have a unique gene signature correlated with poor prognosis of colorectal cancer","volume":"12","author":"Nishina","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3731","DOI":"10.1016\/S0021-9258(17)41921-1","article-title":"Mitogen-activated protein kinases and ribosomal S6 protein kinases are involved in signaling pathways shared by interleukin-11, interleukin-6, leukemia inhibitory factor, and oncostatin M in mouse 3T3-L1 cells","volume":"269","author":"Yin","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4638","DOI":"10.7150\/jca.56185","article-title":"IL-11 mediates the Radioresistance of Cervical Cancer Cells via the PI3K\/Akt Signaling Pathway","volume":"12","author":"Sun","year":"2021","journal-title":"J. Cancer"},{"key":"ref_21","first-page":"195","article-title":"Activation of Src-family protein tyrosine kinases and phosphatidylinositol 3-kinase in 3T3-L1 mouse preadipocytes by interleukin-11","volume":"24","author":"Fuhrer","year":"1996","journal-title":"Exp. Hematol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1016\/S0015-0282(97)81438-0","article-title":"Detection of immunoreactive interleukin-11 in human follicular fluid: Correlations with ovarian steroid, insulin-like growth factor I levels, and follicular maturity","volume":"67","author":"Branisteanu","year":"1997","journal-title":"Fertil. Steril."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2437","DOI":"10.1071\/RD16460","article-title":"Regulation of interleukin-11 expression in ovulatory follicles of the rat ovary","volume":"29","author":"Jang","year":"2017","journal-title":"Reprod. Fertil. Dev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"7218","DOI":"10.12659\/MSM.916385","article-title":"The Effect of Interleukin-6 (IL-6), Interleukin-11 (IL-11), Signal Transducer and Activator of Transcription 3 (STAT3), and AKT Signaling on Adipocyte Proliferation in a Rat Model of Polycystic Ovary Syndrome","volume":"25","author":"Zhuang","year":"2019","journal-title":"Med. Sci. Monit."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1093\/molehr\/gaz033","article-title":"Successful reversal of ovarian hyperstimulation syndrome in a mouse model by rapamycin, an mTOR pathway inhibitor","volume":"25","author":"Liu","year":"2019","journal-title":"Mol. Hum. Reprod."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1071\/RD14128","article-title":"Interleukin 11: Similar or opposite roles in female reproduction and reproductive cancer?","volume":"28","author":"Winship","year":"2016","journal-title":"Reprod. Fertil. Dev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"119135","DOI":"10.1016\/j.bbamcr.2021.119135","article-title":"The role of proteolysis in interleukin-11 signaling","volume":"1869","author":"Lokau","year":"2022","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1006\/jsre.2002.6542","article-title":"IL-11 pretreatment reduces cell death after intestinal ischemia-reperfusion","volume":"108","author":"Kuenzler","year":"2002","journal-title":"J. Surg. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/j.clinre.2015.11.009","article-title":"Interleukin-11 protects mouse liver from warm ischemia\/reperfusion (WI\/Rp) injury","volume":"40","author":"Yu","year":"2016","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.mce.2016.11.002","article-title":"Fibroblast growth factor 9 (FGF9) regulation of cyclin D1 and cyclin-dependent kinase-4 in ovarian granulosa and theca cells of cattle","volume":"440","author":"Totty","year":"2017","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.theriogenology.2018.03.034","article-title":"Effect of inhibin A on proliferation of porcine granulosa cells in vitro","volume":"114","author":"Li","year":"2018","journal-title":"Theriogenology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.canlet.2016.01.004","article-title":"The role of IL-11 in immunity and cancer","volume":"373","author":"Xu","year":"2016","journal-title":"Cancer Lett."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2548","DOI":"10.1038\/sj.onc.1203551","article-title":"Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors","volume":"19","author":"Hirano","year":"2000","journal-title":"Oncogene"},{"key":"ref_34","first-page":"136","article-title":"Targeting the STAT3 signaling pathway in cancer: Role of synthetic and natural inhibitors","volume":"1845","author":"Siveen","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2234","DOI":"10.1158\/1535-7163.MCT-17-0148","article-title":"JAK1\/STAT3 Activation through a Proinflammatory Cytokine Pathway Leads to Resistance to Molecularly Targeted Therapy in Non-Small Cell Lung Cancer","volume":"16","author":"Shien","year":"2017","journal-title":"Mol. Cancer Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1093\/molehr\/4.11.1071","article-title":"Expression of interleukin-6 and interleukin-6 receptors in human granulosa lutein cells","volume":"4","author":"Keck","year":"1998","journal-title":"Mol. Hum. Reprod."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1677\/joe.0.1700471","article-title":"Interaction of interleukin-6 on human granulosa cell steroid secretion","volume":"170","author":"Salmassi","year":"2001","journal-title":"J. Endocrinol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1095\/biolreprod58.5.1266","article-title":"Effects of interleukin (IL)-6 on luteinizing hormone- and IL-1beta-induced ovulation and steroidogenesis in the rat ovary","volume":"58","author":"Woodhouse","year":"1998","journal-title":"Biol. Reprod."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1210\/endo.132.2.8425493","article-title":"Effects and interactions of prostaglandin F2 alpha, oxytocin, and cytokines on steroidogenesis of porcine luteal cells","volume":"132","author":"Pitzel","year":"1993","journal-title":"Endocrinology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1095\/biolreprod50.1.38","article-title":"Effects of interleukin-6 on proliferation and follicle-stimulating hormone-induced estradiol production by bovine granulosa cells in vitro: Dependence on size of follicle","volume":"50","author":"Alpizar","year":"1994","journal-title":"Biol. Reprod."},{"key":"ref_41","first-page":"292","article-title":"Functional interactions, phosphorylation, and levels of 3\u2032,5\u2032-cyclic adenosine monophosphate-regulatory element binding protein and steroidogenic factor-1 mediate hormone-regulated and constitutive expression of aromatase in gonadal cells","volume":"11","author":"Carlone","year":"1997","journal-title":"Mol. Endocrinol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1016\/j.cellsig.2006.02.011","article-title":"FSH signaling pathways in immature granulosa cells that regulate target gene expression: Branching out from protein kinase A","volume":"18","author":"Maizels","year":"2006","journal-title":"Cell. Signal."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1007\/s11010-006-9185-8","article-title":"Real-time monitoring of cAMP response element binding protein signaling in porcine granulosa cells modulated by ovarian factors","volume":"290","author":"He","year":"2006","journal-title":"Mol. Cell. Biochem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3353","DOI":"10.1210\/endo.139.7.6188","article-title":"Follicle stimulating hormone (FSH) activates the p38 mitogen-activated protein kinase pathway, inducing small heat shock protein phosphorylation and cell rounding in immature rat ovarian granulosa cells","volume":"139","author":"Maizels","year":"1998","journal-title":"Endocrinology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1677\/joe.1.05955","article-title":"Activation of the p38 MAPK pathway by follicle-stimulating hormone regulates steroidogenesis in granulosa cells differentially","volume":"186","author":"Yu","year":"2005","journal-title":"J. Endocrinol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1126\/science.1171396","article-title":"MAPK3\/1 (ERK1\/2) in ovarian granulosa cells are essential for female fertility","volume":"324","author":"Fan","year":"2009","journal-title":"Science"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.mce.2017.08.018","article-title":"Lithium chloride inhibits StAR and progesterone production through GSK-3\u03b2 and ERK1\/2 signaling pathways in human granulosa-lutein cells","volume":"461","author":"Bai","year":"2018","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3704","DOI":"10.1210\/endo.138.9.5317","article-title":"The 5\u2032-flanking region of the ovarian promoter of the bovine CYP19 gene contains a deletion in a cyclic adenosine 3\u2032,5\u2032-monophosphate-like responsive sequence","volume":"138","author":"Hinshelwood","year":"1997","journal-title":"Endocrinology"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/4\/673\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:37:34Z","timestamp":1760121454000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/4\/673"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,20]]},"references-count":48,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["cells12040673"],"URL":"https:\/\/doi.org\/10.3390\/cells12040673","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,20]]}}}