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Research Article

TLR3-mediated NF-B signaling in human esophageal epithelial cells

¹Children's Hospital of Philadelphia ²University of Pennsylvania School of Medicine

Submitted 23 February 2009 ; revision received 20 September 2009 ; accepted in final form 21 September 2009

ABSTRACT

Background and Aims: Despite its position at the front-line against ingested pathogens, very little is currently known about the role of the esophageal epithelium in host innate immune defense. As key players in the innate immune response, toll-like receptor (TLR) signaling has not been well-characterized in human esophageal epithelial cells. In the current study, we investigated the inflammatory response and signaling pathways activated by TLR stimulation of human esophageal cells in vitro. Methods and Results: Using quantitative RT-PCR, we profiled the expression pattern of human TLRs 1-10 in primary esophageal keratinocytes (EPC2), immortalized non-transformed esophageal keratinocytes (EPC2-hTERT), and normal human esophageal mucosal biopsies, and found that TLRs 1, 2, 3, and 5 were expressed both in vivo and in vitro. Using the cytokine IL-8 as a physiologic readout of the inflammatory response, we found that TLR3 is the most functional of the expressed TLRs in both primary and immortalized esophageal epithelial cell lines in response to its synthetic ligand polyinosinic polycytidylic acid [poly(I:C)]. Through reporter gene studies, we show that poly(I:C)-induced NF-B activation is critical for the transactivation of the IL-8 promoter in vitro, and that nuclear translocation of NF-B occurs at an early time point following poly(I:C) stimulation of esophageal epithelial cells. Importantly, we also show that poly(I:C) stimulation induces the NF-B -dependent esophageal epithelial expression of TLR2, leading to enhanced epithelial responsiveness of EPC2-hTERT cells to TLR2 ligand stimulation, suggesting an important regulatory role for TLR3-mediated NF-B signaling in the innate immune response of esophageal epithelial cells. Conclusions: Our findings demonstrate for the first time that TLR3 is highly functional in the human esophageal epithelium, and that TLR3-mediated NF-B-signaling may play an important regulatory role in esophageal epithelial homeostasis.

TLR3; esophagus; NF-kB