Flagellin/TLR5 responses in epithelia reveal intertwined activation of inflammatory and apoptotic pathways.
Flagellin, the primary structural component of bacterial flagella, is recognized by Toll-like receptor 5 (TLR5) present on the basolateral surface of intestinal epithelial cells. Utilizing biochemical assays of proinflammatory signaling pathways and mRNA expression profiling, we found that purified flagellin could recapitulate the human epithelial cell proinflammatory responses activated by flagellated pathogenic bacteria. Flagellin-induced proinflammatory activation showed similar kinetics and gene specificity as that induced by the classical endogenous proinflammatory cytokine TNF-alpha, although both responses were more rapid than that elicited by viable flagellated bacteria. Flagellin, like TNF-alpha, activated a number of antiapoptotic mediators, and pretreatment of epithelial cells with this bacterial protein could protect cells from subsequent bacterially mediated apoptotic challenge. However, when NF-kappaB-mediated or phosphatidylinositol 3-kinase/Akt proinflammatory signaling was blocked, flagellin could induce programmed cell death. Consistently, we demonstrate that flagellin and viable flagellate Salmonella induces both the extrinsic and intrinsic caspase activation pathways, with the extrinsic pathway (caspase 8) activated by purified flagellin in a TLR5-dependant fashion. We conclude that interaction of flagellin with epithelial cells induces caspase activation in parallel with proinflammatory responses. Such intertwining of proinflammatory and apoptotic signaling mediated by bacterial products suggests roles for host programmed cell death in the pathogenesis of enteric infections.
Zeng
Hui
H
Epithelial Pathobiology Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 105-F Whitehead Bldg., 615 Michaels St., Atlanta, GA 30322, USA.
Wu
Huixia
H
Sloane
Valerie
V
Jones
Rheinallt
R
Yu
Yimin
Y
Lin
Patricia
P
Gewirtz
Andrew T
AT
Neish
Andrew S
AS
D017209:Apoptosis; D020169:Caspases / Q000235:genetics; D002460:Cell Line; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology*; D005408:Flagellin / Q000378:metabolism*; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000382:microbiology; D016328:NF-kappa B / Q000378:metabolism; D012486:Salmonella typhimurium / Q000502:physiology*; D015398:Signal Transduction; D051198:Toll-Like Receptor 5 / Q000378:metabolism*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
D016328:NF-kappa B; C495346:TLR5 protein, human; D051198:Toll-Like Receptor 5; D014409:Tumor Necrosis Factor-alpha; D005408:Flagellin; D020169:Caspases