title: A novel TLR4-mediated signaling pathway leading to IL-6 responses in human bladder epithelial cells.
abstract: The vigorous cytokine response of immune cells to Gram-negative bacteria is primarily mediated by a recognition molecule, Toll-like receptor 4 (TLR4), which recognizes lipopolysaccharide (LPS) and initiates a series of intracellular NF-kappaB-associated signaling events. Recently, bladder epithelial cells (BECs) were reported to express TLR4 and to evoke a vigorous cytokine response upon exposure to LPS. We examined intracellular signaling events in human BECs leading to the production of IL-6, a major urinary cytokine, following activation by Escherichia coli and isolated LPS. We observed that in addition to the classical NF-kappaB-associated pathway, TLR4 triggers a distinct and more rapid signaling response involving, sequentially, Ca(2+), adenylyl cyclase 3-generated cAMP, and a transcriptional factor, cAMP response element-binding protein. This capacity of BECs to mobilize secondary messengers and evoke a more rapid IL-6 response might be critical in their role as first responders to microbial challenge in the urinary tract.
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Jeongmin
authors.initials: J
authors.lastname: Song
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Duncan
authors.forename: Guojie
authors.initials: G
authors.lastname: Li
authors.forename: Cheryl
authors.initials: C
authors.lastname: Chan
authors.forename: Richard
authors.initials: R
authors.lastname: Grady
authors.forename: Ann
authors.initials: A
authors.lastname: Stapleton
authors.forename: Soman N
authors.initials: SN
authors.lastname: Abraham
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics; D050882:CREB-Binding Protein / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D004926:Escherichia coli / Q000235:genetics / Q000276:immunology*; D004927:Escherichia coli Infections / Q000276:immunology*; D010861:Fimbriae, Bacterial / Q000276:immunology; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D012329:RNA, Bacterial; D015398:Signal Transduction / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D001743:Urinary Bladder / Q000166:cytology / Q000276:immunology* / Q000382:microbiology
chemical_list: D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012329:RNA, Bacterial; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D000242:Cyclic AMP; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D000262:Adenylyl Cyclases; D002118:Calcium