a novel tlr4-mediated signaling pathway leading to il-6 responses in human bladder epithelial cells一种新型tlr4-mediated信号通路导致人类膀胱上皮细胞il - 6的反应.pdfVIP

A Novel TLR4-Mediated Signaling Pathway Leading to IL-6 Responses in Human Bladder Epithelial Cells 1 1 2 3 4 5 Jeongmin Song , Matthew J. Duncan , Guojie Li , Cheryl Chan , Richard Grady , Ann Stapleton , Soman N. Abraham1,2,6* 1 Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America, 2 Department of Pathology, Duke University Medical Center, Durham, North Carolina, United States of America, 3 Program in Cell and Molecular Biology, Duke University Medical Center, Durham, North Carolina, United States of America, 4 Children’s Hospital and Regional Medical Center, Seattle, Washington, United States of America, 5 Department of Microbiology, University of Washington, Seattle, Washington, United States of America, 6 Department of Immunology, Duke University Medical Center, Durham, North Carolina, United States of America 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-jB–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-jB–associated pathway, TLR4 triggers a distinct and more rapid signaling 2þ response involving, sequentially, Ca , adenylyl cyclase 3–generated cAMP, and a transcri