Shiga toxins induce, superinduce, and stabilize a variety of C-X-C chemokine mRNAs in intestinal epithelial cells, resulting in increased chemokine expression

Exposure of humans to Shiga toxins (Stxs) is a risk factor for hemolytic-ur emic syndrome (HUS). Because Stx-producing Escherichia coli (STEC) is a non invasive enteric pathogen, the extent to which Stxs can cross the host inte stinal epithelium may affect the risk of developing HUS. We have previously shown that Stxs can induce and superinduce IL-8 mRNA and protein in intest inal epithelial cells (IECs) in vitro via a ribotoxic stress response. We u sed cytokine expression arrays to determine the effect of Stx1 on various C -X-C chemokine genes in IECs. We observed that Stx1 induces multiple C-X-C chemokines at the mRNA level, including interleukin-8 (IL-8), GRO-alpha, GR O-beta, GRO-gamma, and ENA-78. Like that of IL-8, GRO-alpha and ENA-78 mRNA s are both induced and superinduced by Stx1. Furthermore, Stx1 induces both IL-8 and GRO-a protein in a dose-response fashion, despite an overall inhi bition in host cell protein synthesis. Stx1 treatment stabilizes both IL-8 and GRO-alpha mRNA. We conclude that Stxs are able to increase mRNA and pro tein levels of multiple C-X-C chemokines in IECs, with increased mRNA stabi lity at least one mechanism involved. We hypothesize that ribotoxic stress is a pathway by which Stxs can alter host signal transduction in IECs, resu lting in the production of multiple chemokine mRNAs, leading to increased e xpression of specific proteins. Taken together, these data suggest that exp osing IECs to Stxs may stimulate a proinflammatory response, resulting in i nflux of acute inflammatory cells and thus contributing to the intestinal t issue damage seen in STEC infection.