Shiga toxins stimulate secretion of interleukin-8 from intestinal epithelial cells

In the 1980s, Shiga toxin (Stx)-producing Escherichia coli O157:H7 (STEC) w as identified as a cause of hemorrhagic colitis in the United States and wa s found to be associated with hemolytic uremic syndrome (HUS), a microangio pathic hemolytic anemia characterized by thrombocytopenia and renal failure . The precise way that Stxs cause hemorrhagic colitis and HUS is unclear. S txs have been thought to cause disease by killing or irreversibly harming s ensitive cells through a nonspecific blockade of mRNA translation, eventual ly resulting in cytotoxicity by preventing synthesis of critical molecules needed to maintain cell integrity. Because STEC is noninvasive, we have bee n exploring the host-toxin response at the level of the gastrointestinal mu cosa, where STEC infection begins. We have found that Stx is capable of int erleukin-8 (IL-8) superinduction in a human colonic epithelial cell line. D espite a general blockade of mRNA translation, Stx treatment results in inc reased IL-8 mRNA as well as increased synthesis and secretion of IL-8 prote in. Our data suggest that an active Stx A subunit is required for this acti vity. Ricin, which has the same enzymatic activity and trafficking pathway as Stx, has similar effects. Exploration of the effects of other protein sy nthesis inhibitors (cycloheximide, anisomycin) suggests a mechanism of gene regulation that is distinct from a general translational blockade. Use of the specific p38/RK inhibitor SB202190 showed that blocking of this pathway results in decreased Stx-mediated IL-8 secretion. Furthermore, Stxs induce d mRNA of the primary response gene c-jun, which was subsequently partially blocked by SB202190. These data suggest a novel model of how Stxs contribu te to disease, namely that Stxs may alter regulation of host cell processes in sensitive cells via activation of at least one member of the mitogen-ac tivated protein kinase family in the p38/RK cascade and induction of c-jun mRNA. Stx-induced increases in chemokine synthesis from intestinal epitheli al cells could be important in augmenting the host mucosal inflammatory res ponse to STEC infection.