{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T21:42:49Z","timestamp":1789767769764,"version":"4.0.1"},"reference-count":34,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,5,5]],"date-time":"2022-05-05T00:00:00Z","timestamp":1651708800000},"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":["2022SKHBDR001"],"award-info":[{"award-number":["2022SKHBDR001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Antimicrobial peptides (AMPs), which are natural antibiotics, protect against pathogens invading the urinary tract. RNase 7 with antimicrobial properties has rapid and powerful suppressive effects against Gram-positive and Gram-negative bacterial infections. However, its detailed antibacterial mechanisms have not been fully determined. Here, we investigate whether RNase 7 had an impact on bladder cells under uropathogenic Escherichia coli (UPEC) infection in a high-glucose environment using in vitro GFP-UPEC-infected bladder cell and PE-labeled TLR4, STAT1, and STAT3 models. We provide evidence of the suppressive effects of RNase 7 on UPEC infection and UPEC-induced inflammatory responses by regulating the JAK\/STAT signaling pathway using JAK inhibitor and STAT inhibitor blocking experiments. Pretreatment with different concentrations of RNase 7 for 24 h concentration-dependently suppressed UPEC invasion in bladder cells (5 \u03bcg\/mL reducing 45%; 25 \u03bcg\/mL reducing 60%). The expressions of TLR4, STAT1, and STAT3 were also downregulated in a concentration-dependent manner after RNase 7 pretreatment (5 \u03bcg\/mL reducing 35%, 54% and 35%; 25 \u03bcg\/mL reducing 60%, 75% and 64%, respectively). RNase 7-induced decrease in UPEC infection in a high-glucose environment not only downregulated the expression of TLR4 protein and the JAK\/STAT signaling pathway but also decreased UPEC-induced secretion of exogenous inflammatory IL-6 and IL-8 cytokines, although IL-8 levels increased in the 25 \u03bcg\/mL RNase 7-treated group. Thus, inhibition of STAT affected pSTAT1, pSTAT3, and TLR4 expression, as well as proinflammatory IL-6 and IFN-\u03b3 expression. Notably, blocking JAK resulted in the rebound expression of related proteins, especially pSTAT1, TLR4, and IL-6. The present study showed the suppressive effects of RNase 7 on UPEC infection and induced inflammation in bladder epithelial cells in a high-glucose environment. RNase 7 may be an anti-inflammatory and anti-infective mediator in bladder cells by downregulating the JAK\/STAT signaling pathway and may be beneficial in treating cystitis in DM patients. These results will help clarify the correlation between AMP production and UTI, identify the relationship between urinary tract infection and diabetes in UTI patients, and develop novel diagnostics or possible treatments targeting RNase 7.<\/jats:p>","DOI":"10.3390\/ijms23095156","type":"journal-article","created":{"date-parts":[[2022,5,5]],"date-time":"2022-05-05T13:10:26Z","timestamp":1651756226000},"page":"5156","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["RNase 7 Inhibits Uropathogenic Escherichia coli-Induced Inflammation in Bladder Cells under a High-Glucose Environment by Regulating the JAK\/STAT Signaling Pathway"],"prefix":"10.3390","volume":"23","author":[{"given":"Chen-Hsun","family":"Ho","sequence":"first","affiliation":[{"name":"Division of Urology, Department of Surgery, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 11101, Taiwan"},{"name":"School of Medicine, Fu Jen Catholic University, New Taipei City 24205, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pin-Wen","family":"Liao","sequence":"additional","affiliation":[{"name":"School of Medicine, Fu Jen Catholic University, New Taipei City 24205, Taiwan"},{"name":"Department of Neurology, Cathay General Hospital, Taipei 10630, Taiwan"},{"name":"Graduate Institute of Neural Regenerative Medicine, College of Medicine Science and Technology, Taipei Medical University, Taipei 11031, 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":[[2022,5,5]]},"reference":[{"key":"ref_1","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_2","first-page":"27","article-title":"Urinary tract infections in women","volume":"95","author":"Dielubanza","year":"2011","journal-title":"Med. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1002\/bdra.23570","article-title":"Association between antibiotic use among pregnant women with urinary tract infections in the first trimester and birth defects, National Birth Defects Prevention Study 1997 to 2011","volume":"106","author":"Ailes","year":"2016","journal-title":"Birth Defects Res. A Clin. Mol. Teratol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.juro.2009.02.124","article-title":"Maintaining a sterile urinary tract: The role of antimicrobial peptides","volume":"182","author":"Ali","year":"2009","journal-title":"J. Urol."},{"key":"ref_5","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_6","doi-asserted-by":"crossref","first-page":"2810","DOI":"10.1681\/ASN.2007050611","article-title":"Antimicrobial peptides, innate immunity, and the normally sterile urinary tract","volume":"18","author":"Zasloff","year":"2007","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"8083","DOI":"10.1021\/bi900914g","article-title":"Mechanisms of antimicrobial, cytolytic, and cell-penetrating peptides: From kinetics to thermodynamics","volume":"48","author":"Almeida","year":"2009","journal-title":"Biochemistry"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1007\/s00249-011-0682-7","article-title":"Antimicrobial peptides with cell-penetrating peptide properties and vice versa","volume":"40","author":"Splith","year":"2011","journal-title":"Eur. Biophys. J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1124\/pr.55.1.2","article-title":"Mechanisms of antimicrobial peptide action and resistance","volume":"55","author":"Yeaman","year":"2003","journal-title":"Pharmacol. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"46779","DOI":"10.1074\/jbc.M207587200","article-title":"RNase 7, a novel innate immune defense antimicrobial protein of healthy human skin","volume":"277","author":"Harder","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1038\/ki.2012.410","article-title":"Ribonuclease 7, an antimicrobial peptide upregulated during infection, contributes to microbial defense of the human urinary tract","volume":"83","author":"Spencer","year":"2013","journal-title":"Kidney Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1016\/j.euf.2016.08.006","article-title":"Urinary Tract Infections in Immunocompromised Patients with Diabetes, Chronic Kidney Disease, and Kidney Transplant","volume":"2","author":"Tandogdu","year":"2016","journal-title":"Eur. Urol. Focus"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"228","DOI":"10.3947\/ic.2018.50.3.228","article-title":"The Predictive Value of Glycated Hemoglobin and Albumin for the Clinical Course Following Hospitalization of Patients with Febrile Urinary Tract Infection","volume":"50","author":"Kobayashi","year":"2018","journal-title":"Infect. Chemother."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"703696","DOI":"10.1155\/2014\/703696","article-title":"Plasma Antimicrobial Peptide LL-37 Level Is Inversely Associated with HDL Cholesterol Level in Patients with Type 2 Diabetes Mellitus","volume":"2014","author":"Meguro","year":"2014","journal-title":"Int. J. Endocrinol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/j.arcmed.2020.03.006","article-title":"Host Defense Peptide RNase 7 Is Down-regulated in the Skin of Diabetic Patients with or without Chronic Ulcers, and its Expression is Altered with Metformin","volume":"51","author":"Trujillo","year":"2020","journal-title":"Arch. Med. Res."},{"key":"ref_16","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_17","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_18","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_19","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_20","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_21","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_22","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1111\/j.1365-2362.2008.02006.x","article-title":"Current concepts of molecular defence mechanisms operative during urinary tract infection","volume":"38","author":"Weichhart","year":"2008","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1038\/nri3887","article-title":"The nature of immune responses to urinary tract infections","volume":"15","author":"Abraham","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.mib.2007.12.001","article-title":"Tlr-Mediated Immune Responses in the Urinary Tract","volume":"11","author":"Song","year":"2008","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_25","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_26","doi-asserted-by":"crossref","first-page":"3340","DOI":"10.4049\/jimmunol.1402169","article-title":"Basal cells contribute to innate immunity of the airway epithelium through production of the antimicrobial protein RNase 7","volume":"194","author":"Amatngalim","year":"2015","journal-title":"J. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Simanski, M., Rademacher, F., Schroder, L., Schumacher, H.M., Glaser, R., and Harder, J. (2013). IL-17A and IFN-gamma synergistically induce RNase 7 expression via STAT3 in primary keratinocytes. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0059531"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e149807","DOI":"10.1172\/JCI149807","article-title":"Ribonuclease 7 polymorphism rs1263872 reduces antimicrobial activity and associates with pediatric urinary tract infections","volume":"131","author":"Pierce","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"477","DOI":"10.2119\/molmed.2012.00024","article-title":"Inhibition of high-mobility group box 1 protein (HMGB1) enhances bacterial clearance and protects against Pseudomonas Aeruginosa pneumonia in cystic fibrosis","volume":"18","author":"Entezari","year":"2012","journal-title":"Mol. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3068","DOI":"10.1073\/pnas.1316925111","article-title":"JAK\/STAT1 signaling promotes HMGB1 hyperacetylation and nuclear translocation","volume":"111","author":"Lu","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1083\/jcb.200911078","article-title":"Endogenous HMGB1 regulates autophagy","volume":"190","author":"Tang","year":"2010","journal-title":"J. Cell Biol."},{"key":"ref_32","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_33","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_34","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. Physiol. Regul. Integr. Comp. Physiol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/9\/5156\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:06:30Z","timestamp":1760137590000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/9\/5156"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,5]]},"references-count":34,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["ijms23095156"],"URL":"https:\/\/doi.org\/10.3390\/ijms23095156","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,5]]}}}