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-κB–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-κB–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.

Author Summary

In spite of frequent cross contamination by bacteria from the gut, urinary tract infections are relatively infrequent. Although much of the credit goes to cells lining the urinary tract, such as bladder cells, how this is achieved remains unclear. Human bladder cells display, on their surfaces, special molecules called Toll-like receptors, which sense the presence of bacteria and trigger the cells to release a variety of chemicals called cytokines. Cytokines contribute to the recruitment of phagocytic cells from the blood to the site of infection to clear bacteria. In this paper, we reveal that the Toll-like receptor–initiated intracellular signals leading to the production of cytokines by bladder cells involve the same pathway seen in other cells, as well as an additional and more rapid signaling pathway. Rapid production of cytokines by bladder cells will facilitate early clearance of bacteria. Additionally, possession of multiple signaling pathways by bladder cells for producing cytokines is advantageous because bacteria that infect the urinary tract have the capability to suppress certain signaling events that lead to cytokine production by bladder cells.