Flagellin is a bacterial protein responsible for activation of toll receptor 5 (TLR5), which we hypothesize is involved in the induction of cytoprotective heat shock proteins in intestinal epithelial cells. Using flagellin derived from the bacterial pathogen, Salmonella typhimurium, our studies confirm that flagellin induces Hsp25 in different intestinal epithelial cell lines in a time- and dose-dependent manner. In addition, Hsp25 induction is observed only when flagellin is added to the basolateral side of polarized intestinal epithelial cells, consistent with the known location of TLR5. The ability of flagellin to induce Hsp25 expression is likely transcriptional as it is abolished by treatment with actinomycin D. It also requires p38 MAP kinase activation, and Western blot analysis indicates that treatment with the p38 MAP kinase inhibitor blocks Hsp25 production. Flagellin-mediated Hsp25 induction is associated with increased protective effects against oxidant stress, an effect that is at least partially mediated by p38 MAP kinase. Use of siRNA against Hsp25 demonstrates that flagellin-mediated protection against oxidant stress is at least partially mediated through Hsp25 induction. In a mouse model of S. typhimurium infection, not only does infection with wild-type and a flagellin-deletion mutant strain of S. typhimurium show that flagellin induces Hsp25 in vivo, it also demonstrates that the major stimulus for Hsp induction is actually flagellin and not LPS. These data provide evidence that flagellin is required for Salmonella-mediated induction of Hsp25 expression in intestinal epithelium. This may explain, in part, why more intestinal damage is seen in mice infected with the aflagellate strain, as opposed to the wild-type strain, of S. typhimurium. Flagellin-induced expression of Hsp25 may be one strategy used by the host to protect itself against the deleterious effects of Salmonella infection.
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