title: Shiga toxins stimulate secretion of interleukin-8 from intestinal epithelial cells.
abstract: In the 1980s, Shiga toxin (Stx)-producing Escherichia coli O157:H7 (STEC) was identified as a cause of hemorrhagic colitis in the United States and was found to be associated with hemolytic uremic syndrome (HUS), a microangiopathic hemolytic anemia characterized by thrombocytopenia and renal failure. The precise way that Stxs cause hemorrhagic colitis and HUS is unclear. Stxs have been thought to cause disease by killing or irreversibly harming sensitive cells through a nonspecific blockade of mRNA translation, eventually resulting in cytotoxicity by preventing synthesis of critical molecules needed to maintain cell integrity. Because STEC is noninvasive, we have been exploring the host-toxin response at the level of the gastrointestinal mucosa, where STEC infection begins. We have found that Stx is capable of interleukin-8 (IL-8) superinduction in a human colonic epithelial cell line. Despite a general blockade of mRNA translation, Stx treatment results in increased IL-8 mRNA as well as increased synthesis and secretion of IL-8 protein. Our data suggest that an active Stx A subunit is required for this activity. Ricin, which has the same enzymatic activity and trafficking pathway as Stx, has similar effects. Exploration of the effects of other protein synthesis 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 induced mRNA of the primary response gene c-jun, which was subsequently partially blocked by SB202190. These data suggest a novel model of how Stxs contribute 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-activated protein kinase family in the p38/RK cascade and induction of c-jun mRNA. Stx-induced increases in chemokine synthesis from intestinal epithelial cells could be important in augmenting the host mucosal inflammatory response to STEC infection.
authors.affiliation: Division of Geographic Medicine, New England Medical Center, Boston, Massachusetts 02111, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Thorpe
authors.forename: B P
authors.initials: BP
authors.lastname: Hurley
authors.forename: L L
authors.initials: LL
authors.lastname: Lincicome
authors.forename: M S
authors.initials: MS
authors.lastname: Jacewicz
authors.forename: G T
authors.initials: GT
authors.lastname: Keusch
authors.forename: D W
authors.initials: DW
authors.lastname: Acheson
mesh_terms: D000841:Anisomycin / Q000494:pharmacology; D001427:Bacterial Toxins / Q000633:toxicity*; D003513:Cycloheximide / Q000494:pharmacology; D016758:Genes, jun; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D022603:Shiga Toxins; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D001427:Bacterial Toxins; D007093:Imidazoles; D016209:Interleukin-8; D011725:Pyridines; D012333:RNA, Messenger; D022603:Shiga Toxins; D014409:Tumor Necrosis Factor-alpha; D000841:Anisomycin; D003513:Cycloheximide; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole