{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T04:01:31Z","timestamp":1780632091430,"version":"3.54.1"},"reference-count":43,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2022,12,12]],"date-time":"2022-12-12T00:00:00Z","timestamp":1670803200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Shin Kong Memorial Wu Ho-Su Hospital, Taipei, Taiwan.","award":["2021SKHBDR002"],"award-info":[{"award-number":["2021SKHBDR002"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>JAK\/STAT plays a key role in regulating uropathogenic Escherichia coli (UPEC) infection in urothelial cells, probably via antimicrobial peptide (AMP) production, in diabetic patients with urinary tract infections. Whether multiple pathways regulate AMPs, especially lipid-carrying protein-2 (LCN2), to achieve a vital effect is unknown. We investigated the effects of an LCN2 pretreatment on the regulation of the JAK\/STAT pathway in a high-glucose environment using a bladder cell model with GFP-UPEC and phycoerythrin-labeled TLR-4, STAT1, and STAT3. Pretreatment with 5 or 25 \u03bcg\/mL LCN2 for 24 h dose-dependently suppressed UPEC infections in bladder cells. TLR-4, STAT1, and STAT3 expression were dose-dependently downregulated after LCN2 pretreatment. The LCN2-mediated alleviation of UPEC infection in a high-glucose environment downregulated TLR-4 and the JAK\/STAT transduction pathway and decreased the UPEC-induced secretion of exogenous inflammatory interleukin (IL)-6 and IL-8. Our study provides evidence that LCN2 can alleviate UPEC infection in bladder epithelial cells by decreasing JAK\/STAT pathway activation in a high-glucose environment. LCN2 dose-dependently inhibits UPEC infection via TLR-4 expression and JAK\/STAT pathway modulation. These findings may provide a rationale for targeting LCN2\/TLR-4\/JAK\/STAT regulation in bacterial cystitis treatment. Further studies should explore specific mechanisms by which the LCN2, TLR-4, and JAK\/STAT pathways participate in UPEC-induced inflammation to facilitate the development of effective therapies for cystitis.<\/jats:p>","DOI":"10.3390\/ijms232415763","type":"journal-article","created":{"date-parts":[[2022,12,13]],"date-time":"2022-12-13T01:56:06Z","timestamp":1670896566000},"page":"15763","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Antimicrobial Peptide LCN2 Inhibited Uropathogenic Escherichia coli Infection in Bladder Cells in a High-Glucose Environment through JAK\/STAT Signaling Pathway"],"prefix":"10.3390","volume":"23","author":[{"given":"Pei-Chi","family":"Chen","sequence":"first","affiliation":[{"name":"Division of Endocrinology and Metabolism, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 11101, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen-Hsun","family":"Ho","sequence":"additional","affiliation":[{"name":"School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 24205, Taiwan"},{"name":"Division of Urology, Department of Surgery, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 11101, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5579-8169","authenticated-orcid":false,"given":"Chia-Kwung","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Molecular Parasitology and Tropical Diseases, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Center for International Tropical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Ping","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Urology, National Taiwan University Hospital and College of Medicine, Taipei 10002, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1172-2485","authenticated-orcid":false,"given":"Po-Ching","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Molecular Parasitology and Tropical Diseases, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Center for International Tropical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S54","DOI":"10.1016\/j.ijantimicag.2007.07.042","article-title":"Urinary tract infections in patients with diabetes mellitus: Epidemiology, pathogenesis and treatment","volume":"31","author":"Geerlings","year":"2008","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1111\/j.0954-6820.1982.tb01983.x","article-title":"Neutrophil and lymphocyte function in patients with diabetes mellitus","volume":"211","author":"Valerius","year":"1982","journal-title":"Acta Med. Scand."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.mcna.2010.08.023","article-title":"Urinary tract infections in women","volume":"95","author":"Dielubanza","year":"2011","journal-title":"Med. Clin. N. Am."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/S0022-5347(17)37160-4","article-title":"Emphysematous cystitis: A review of the spectrum of disease","volume":"147","author":"Quint","year":"1992","journal-title":"J. Urol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"80S","DOI":"10.1016\/S0002-9343(02)01062-8","article-title":"Urinary tract infections in patients with diabetes","volume":"113","author":"Stapleton","year":"2002","journal-title":"Am. J. Med."},{"key":"ref_6","first-page":"129","article-title":"Emphysematous cystitis in a patient with type 2 diabetes mellitus","volume":"65","author":"Toyota","year":"2011","journal-title":"Acta Med. Okayama"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/j.mpmed.2007.05.009","article-title":"Urinary tract infection","volume":"35","author":"Lee","year":"2007","journal-title":"Medicine"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1016\/j.eururo.2008.05.010","article-title":"Surveillance Study in Europe and Brazil on Clinical Aspects and Antimicrobial Resistance Epidemiology in Females with Cystitis (ARESC): Implications for Empiric Therapy","volume":"54","author":"Naber","year":"2008","journal-title":"Eur. Urol."},{"key":"ref_9","first-page":"295","article-title":"Bacterial cystitis in women","volume":"39","author":"Chung","year":"2010","journal-title":"Aust. Fam. Physician"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1002\/sm2.17","article-title":"Multidisciplinary Overview of Vaginal Atrophy and Associated Genitourinary Symptoms in Postmenopausal Women","volume":"1","author":"Goldstein","year":"2013","journal-title":"Sex. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1053\/j.ajkd.2005.05.019","article-title":"Host and bacterial virulence factors predisposing to emphysematous pyelonephritis","volume":"46","author":"Tseng","year":"2005","journal-title":"Am. J. Kidney Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2661","DOI":"10.1681\/ASN.2006121410","article-title":"Reduced expression of insulin receptors in the kidneys of insulin-resistant rats","volume":"18","author":"Tiwari","year":"2007","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1038\/nrneph.2015.105","article-title":"Amplifying renal immunity: The role of antimicrobial peptides in pyelonephritis","volume":"11","author":"Becknell","year":"2015","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2963","DOI":"10.1172\/JCI71630","article-title":"alpha-Intercalated cells defend the urinary system from bacterial infection","volume":"124","author":"Paragas","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1016\/j.kint.2016.04.025","article-title":"Insulin and the phosphatidylinositol 3-kinase signaling pathway regulate Ribonuclease 7 expression in the human urinary tract","volume":"90","author":"Eichler","year":"2016","journal-title":"Kidney Int."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.molmet.2015.05.001","article-title":"Knockout of STAT3 in skeletal muscle does not prevent high-fat diet-induced insulin resistance","volume":"4","author":"White","year":"2015","journal-title":"Mol. Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"5634","DOI":"10.1172\/JCI98595","article-title":"Insulin receptor signaling regulates renal collecting duct and intercalated cell antibacterial defenses","volume":"128","author":"Murtha","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1016\/j.cell.2007.06.009","article-title":"AKT\/PKB signaling: Navigating downstream","volume":"129","author":"Manning","year":"2007","journal-title":"Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.1007\/s40618-020-01494-0","article-title":"Lipocalin-2: A role in hepatic gluconeogenesis via AMP-activated protein kinase (AMPK)","volume":"44","author":"Sun","year":"2021","journal-title":"J. Endocrinol. Investig."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Ho, C.H., Liu, S.P., Fan, C.K., Tzou, K.Y., Wu, C.C., and Cheng, P.C. (2021). Insulin Downregulated the Infection of Uropathogenic Escherichia coli (UPEC) in Bladder Cells in a High-Glucose Environment through JAK\/STAT Signaling Pathway. Microorganisms, 9.","DOI":"10.3390\/microorganisms9122421"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1016\/j.immuni.2012.03.014","article-title":"JAK and STAT signaling molecules in immunoregulation and immune-mediated disease","volume":"36","author":"Plenge","year":"2012","journal-title":"Immunity"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"457","DOI":"10.2337\/db12-0337","article-title":"Constitutive STAT3 phosphorylation contributes to skeletal muscle insulin resistance in type 2 diabetes","volume":"62","author":"Mashili","year":"2013","journal-title":"Diabetes"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/s00592-011-0259-z","article-title":"IL-6 induction of TLR-4 gene expression via STAT3 has an effect on insulin resistance in human skeletal muscle","volume":"50","author":"Kim","year":"2013","journal-title":"Acta Diabetol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1186\/s13098-015-0086-4","article-title":"High glucose induces and activates Toll-like receptor 4 in endothelial cells of diabetic retinopathy","volume":"7","author":"Wang","year":"2015","journal-title":"Diabetol. Metab. Syndr."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1210\/jc.2007-2185","article-title":"Increased toll-like receptor (TLR) 2 and TLR4 expression in monocytes from patients with type 1 diabetes: Further evidence of a proinflammatory state","volume":"93","author":"Devaraj","year":"2008","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.jmii.2019.05.008","article-title":"Enhanced uropathogenic Escherichia coli-induced infection in uroepithelial cells by sugar through TLR-4 and JAK\/STAT1 signaling pathways","volume":"54","author":"Ho","year":"2021","journal-title":"J. Microbiol. Immunol. Infect."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Ho, C.H., Fan, C.K., Yu, H.J., Wu, C.C., Chen, K.C., Liu, S.P., and Cheng, P.C. (2017). Testosterone suppresses uropathogenic Escherichia coli invasion and colonization within prostate cells and inhibits inflammatory responses through JAK\/STAT-1 signaling pathway. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0190317"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Ho, C.H., Liao, P.W., Fan, C.K., Liu, S.P., and Cheng, P.C. (2022). RNase 7 Inhibits Uropathogenic Escherichia coli-Induced Inflammation in Bladder Cells under a High-Glucose Environment by Regulating the JAK\/STAT Signaling Pathway. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23095156"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.7754\/Clin.Lab.2017.170313","article-title":"The Effects of Insulin and Glucose on Different Characteristics of a UPEC: Alterations in Growth Rate and Expression Levels of some Virulence Genes","volume":"63","author":"Gumus","year":"2017","journal-title":"Clin. Lab."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"151450","DOI":"10.1016\/j.ijmm.2020.151450","article-title":"Testosterone regulates the intracellular bacterial community formation of uropathogenic Escherichia coli in prostate cells via STAT3","volume":"310","author":"Ho","year":"2020","journal-title":"Int. J. Med. Microbiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"6081","DOI":"10.4049\/jimmunol.1401528","article-title":"Lipocalin 2 imparts selective pressure on bacterial growth in the bladder and is elevated in women with urinary tract infection","volume":"193","author":"Steigedal","year":"2014","journal-title":"J. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Kluber, P., Meurer, S.K., Lambertz, J., Schwarz, R., Zechel-Gran, S., Braunschweig, T., Hurka, S., Domann, E., and Weiskirchen, R. (2021). Depletion of Lipocalin 2 (LCN2) in Mice Leads to Dysbiosis and Persistent Colonization with Segmented Filamentous Bacteria. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222313156"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"107587","DOI":"10.1016\/j.intimp.2021.107587","article-title":"miR-383 reduces keratinocyte proliferation and induces the apoptosis in psoriasis via disruption of LCN2-dependent JAK\/STAT pathway activation","volume":"96","author":"Wang","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/j.bbrc.2013.03.117","article-title":"Induction mechanism of lipocalin-2 expression by co-stimulation with interleukin-1beta and interferon-gamma in RINm5F beta-cells","volume":"434","author":"Chang","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1111\/j.1600-0463.2012.02951.x","article-title":"Expression of suppressor of cytokine signalling 3 (SOCS3) in human bladder epithelial cells infected with uropathogenic Escherichia coli","volume":"121","author":"Demirel","year":"2013","journal-title":"APMIS"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1038\/nri2093","article-title":"SOCS proteins, cytokine signalling and immune regulation","volume":"7","author":"Yoshimura","year":"2007","journal-title":"Nat. Rev. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"a011205","DOI":"10.1101\/cshperspect.a011205","article-title":"The Jak\/STAT pathway","volume":"4","author":"Harrison","year":"2012","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3257","DOI":"10.1167\/iovs.15-18993","article-title":"Acute Stress Responses Are Early Molecular Events of Retinal Degeneration in Abca4-\/-Rdh8-\/- Mice After Light Exposure","volume":"57","author":"Parmar","year":"2016","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3336","DOI":"10.1111\/jcmm.14224","article-title":"PECAM-1 modulates liver damage induced by synergistic effects of TNF-alpha and irradiation","volume":"23","author":"Malik","year":"2019","journal-title":"J. Cell Mol. Med."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Saldana, Z., De la Cruz, M.A., Carrillo-Casas, E.M., Duran, L., Zhang, Y., Hernandez-Castro, R., Puente, J.L., Daaka, Y., and Giron, J.A. (2014). Production of the Escherichia coli common pilus by uropathogenic E. coli is associated with adherence to HeLa and HTB-4 cells and invasion of mouse bladder urothelium. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0101200"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2762","DOI":"10.1128\/IAI.00323-09","article-title":"Urothelial cultures support intracellular bacterial community formation by uropathogenic Escherichia coli","volume":"77","author":"Berry","year":"2009","journal-title":"Infect. Immun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1016\/j.neurobiolaging.2006.12.003","article-title":"Association between IL-8 cytokine and cognitive performance in an elderly general population\u2014The MEMO-Study","volume":"29","author":"Baune","year":"2008","journal-title":"Neurobiol. Aging"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"R738","DOI":"10.1152\/ajpregu.00145.2005","article-title":"Short-term stress experienced at time of immunization induces a long-lasting increase in immunologic memory","volume":"289","author":"Dhabhar","year":"2005","journal-title":"Am. J. Physiology. Regul. Integr. Comp. Physiol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/24\/15763\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:39:53Z","timestamp":1760146793000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/24\/15763"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,12]]},"references-count":43,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["ijms232415763"],"URL":"https:\/\/doi.org\/10.3390\/ijms232415763","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,12]]}}}