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Type: Journal article
Title: Shiga toxin 2 and Flagellin from Shiga-toxigenic Escherichia coli superinduce interleukin-8 through synergistic effects on host stress-activated protein kinase activation
Author: Jandhyala, D.
Rogers, T.
Kane, A.
Paton, A.
Paton, J.
Thorpe, C.
Citation: Infection and Immunity, 2010; 78(7):2984-2994
Publisher: Amer Soc Microbiology
Issue Date: 2010
ISSN: 0019-9567
Statement of
Dakshina M. Jandhyala, Trisha J. Rogers, Anne Kane, Adrienne W. Paton, James C. Paton and Cheleste M. Thorpe
Abstract: Shiga toxins expressed in the intestinal lumen during infection with Shiga-toxigenic Escherichia coli must translocate across the epithelium and enter the systemic circulation to cause systemic (pathological) effects, including hemolytic uremic syndrome. The transepithelial migration of polymorphonuclear leukocytes in response to chemokine expression by intestinal epithelial cells is thought to promote uptake of Stx from the intestinal lumen by compromising the epithelial barrier. In the present study, we investigated the hypothesis that flagellin acts in conjunction with Shiga toxin to augment this chemokine expression. We investigated the relative contributions of nuclear factor B (NF-B) and mitogen-activated protein kinase (MAPK) signaling to transcription and translation of interleukin-8. Using reporter gene constructs, we showed that flagellin-mediated interleukin-8 gene transcription is heavily dependent on both NF-B and extracellular signal-regulated kinase 1 and 2 (ERK-1/2) activation. In contrast, inhibition of p38 has no detectable effect on interleukin-8 gene transcription, even though flagellin-mediated activation of host p38 is critical for maximal interleukin-8 protein expression. Inhibition of MAPK-interacting kinase 1 suggests that p38 signaling affects the posttranscriptional regulation of interleukin-8 protein expression induced by flagellin. Cotreatment with Stx2 and flagellin results in a synergistic upregulation of c-Jun N-terminal protein kinases (JNKs), p38 activation, and a superinduction of interleukin-8 mRNA. This synergism was also evident at the protein level, with increased interleukin-8 protein detectable following cotreatment with flagellin and Stx2. We propose that flagellin, in conjunction with Shiga toxin, synergistically upregulates stress-activated protein kinases, resulting in superinduction of interleukin-8 and, ultimately, absorption of Stx into the systemic circulation.
Keywords: Cell Line
Escherichia coli Infections
Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
p38 Mitogen-Activated Protein Kinases
NF-kappa B
Fluorescent Antibody Technique, Indirect
Enzyme-Linked Immunosorbent Assay
Cloning, Molecular
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Enzyme Activation
Shiga Toxin 2
Shiga-Toxigenic Escherichia coli
Rights: Copyright © 2010, American Society for Microbiology. All Rights Reserved
DOI: 10.1128/IAI.00383-10
Appears in Collections:Aurora harvest
Molecular and Biomedical Science publications

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