Shiga toxins activate translational regulation pathways in intestinal epithelial cells

Colpoys, W.E.; Cochran, Brent; Carducci, Tessa M.; Thorpe, Cheleste M.

doi:10.1016/j.cellsig.2004.11.014

Cited by 26 publications

(24 citation statements)

References 42 publications

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“…Previously, we reported that Stx1-induced ERK1/2 activation in HCT-8 cells contributed to the phosphorylation of the eukaryotic initiation factor eIF4E and, as a result, translational reprogramming (12). However, in that study we did not further characterize the ERK1/2 activation by Stx1.…”

Section: Shiga Toxin 1 Induces Erk1/2 In a Biphasic Manner In Iecscontrasting

confidence: 48%

“…While ERK1/2 activation by Stx1 previously has been demonstrated in macrophage-like THP-1 cells (14), in the ACHN renal tubule-derived cell line (32), and by members of our group in HCT-8 cells (12), the mechanism by which ERK1/2 activation occurred in these studies was not investigated further. In vitro studies have suggested that intestinal inflammation promotes the systemic uptake of Stx through disruption of the epithelial tight junction during neutrophil influx into the lumen (33).…”

Section: Discussionmentioning

confidence: 99%

“…Different groups (including ours) have observed Stx-induced ERK1/2 activation (12)(13)(14)(15), but the mechanism(s) by which this occurs has not been studied in depth, and the potential contribu-tion of ERK1/2 signaling to disease has not been well studied. Some cell lines respond to Stx with ERK1/2 activation, but others do not (D. M. Jandhyala and C. M. Thorpe, unpublished data) (6,15,16).…”

mentioning

confidence: 99%

“…Furthermore, in order for the ribotoxic stress response to occur, ribosomes must be actively engaged in protein synthesis, as pretreatment with protein synthesis inhibitors such as emetine, a protein synthesis inhibitor that inactivates ribosomes by stabilizing the 80S polysome (8), or pactamycin, which blocks translational initiation, prevents the RSR (4,9). Concomitant with the Stx-induced RSR is an upregulation of proinflammatory mRNAs, as well as a paradoxical expression of proinflammatory cytokine proteins, and it is well established that blocking host MAPKs blocks Stx-induced proinflammatory cytokine expression (6,(10)(11)(12)(13)(14).…”

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confidence: 99%

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Activation of the Classical Mitogen-Activated Protein Kinases Is Part of the Shiga Toxin-Induced Ribotoxic Stress Response and May Contribute to Shiga Toxin-Induced Inflammation

et al. 2016

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c Infection with enterohemorrhagic Escherichia coli (EHEC) can result in severe disease, including hemorrhagic colitis and the hemolytic uremic syndrome. Shiga toxins (Stx) are the key EHEC virulence determinant contributing to severe disease. Despite inhibiting protein synthesis, Shiga toxins paradoxically induce the expression of proinflammatory cytokines from various cell types in vitro, including intestinal epithelial cells (IECs). This effect is mediated in large part by the ribotoxic stress response (RSR). The Shiga toxin-induced RSR is known to involve the activation of the stress-activated protein kinases (SAPKs) p38 and JNK. In some cell types, Stx also can induce the classical mitogen-activated protein kinases (MAPKs) or ERK1/2, but the mechanism(s) by which this activation occurs is unknown. In this study, we investigated the mechanism by which Stx activates ERK1/2s in IECs and the contribution of ERK1/2 activation to interleukin-8 (IL-8) expression. We demonstrate that Stx1 activates ERK1/2 in a biphasic manner: the first phase occurs in response to StxB1 subunit, while the second phase requires StxA1 subunit activity. We show that the A subunit-dependent ERK1/2 activation is mediated through ZAK-dependent signaling, and inhibition of ERK1/2 activation via the MEK1/2 inhibitors U0126 and PD98059 results in decreased Stx1-mediated IL-8 mRNA. Finally, we demonstrate that ERK1/2 are activated in vivo in the colon of Stx2-intoxicated infant rabbits, a model in which Stx2 induces a primarily neutrophilic inflammatory response. Together, our data support a role for ERK1/2 activation in the development of Stx-mediated intestinal inflammation.

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Section: Shiga Toxin 1 Induces Erk1/2 In a Biphasic Manner In Iecscontrasting

confidence: 48%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Activation of the Classical Mitogen-Activated Protein Kinases Is Part of the Shiga Toxin-Induced Ribotoxic Stress Response and May Contribute to Shiga Toxin-Induced Inflammation

et al. 2016

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“…However, the myriad signaling pathways activated by Stxs may potentially regulate the expression of large numbers of genes (6). Therefore, we carried out comparative microarray analyses to help explore global transcriptional responses of macrophage-like THP-1 cells treated with Stx1 or the well-characterized bacterial outer membrane constituent lipopolysaccharides (LPS).…”

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confidence: 99%

Global Transcriptional Response of Macrophage-Like THP-1 Cells to Shiga Toxin Type 1

et al. 2010

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Shiga toxins (Stxs) are bacterial cytotoxins produced by the enteric pathogens Shigella dysenteriae serotype 1 and some serotypes of Escherichia coli that cause bacillary dysentery and hemorrhagic colitis, respectively. To date, approaches to studying the capacity of Stxs to alter gene expression in intoxicated cells have been limited to individual genes. However, it is known that many of the signaling pathways activated by Stxs regulate the expression of multiple genes in mammalian cells. To expand the scope of analysis of gene expression and to better understand the underlying mechanisms for the various effects of Stxs on host cell functions, we carried out comparative microarray analyses to characterize the global transcriptional response of human macrophage-like THP-1 cells to Shiga toxin type 1 (Stx1) and lipopolysaccharides. The data were analyzed by using a rigorous combinatorial approach with three separate statistical algorithms. A total of 36 genes met the criteria of upregulated expression in response to Stx1 treatment, with 14 genes uniquely upregulated by Stx1. Microarray data were validated by real-time reverse transcriptase PCR for genes encoding early growth response 1 (Egr-1) (transcriptional regulator), cyclooxygenase 2 (COX-2; inflammation), and dual specificity phosphatase 1 (DUSP1), DUSP5, and DUSP10 (regulation of mitogen-activated protein kinase signaling). Stx1-mediated signaling through extracellular signal-regulated kinase 1/2 and Egr-1 appears to be involved in the increased expression and production of the proinflammatory mediator tumor necrosis factor alpha. Activation of COX-2 is associated with the increased production of proinflammatory and vasoactive eicosanoids. However, the capacity of Stx1 to increase the expression of genes encoding phosphatases suggests that mechanisms to dampen the macrophage proinflammatory response may be built into host response to the toxins.

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Ricin and Shiga Toxins: Effects on Host Cell Signal Transduction

Jandhyala

Thorpe

Magun

2011

Current Topics in Microbiology and Immunology

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Shiga toxins and ricin are potent inhibitors of protein synthesis. In addition to causing inhibition of protein synthesis, these toxins activate proinflammatory signaling cascades that may contribute to the severe diseases associated with toxin exposure. Treatment of cells with Shiga toxins and ricin have been shown to activate a number of signaling pathways including those associated with the ribotoxic stress response, Nuclear factor kappa B activation, inflammasome activation, the unfolded protein response, mTOR signaling, hemostasis, and retrograde trafficking. In this chapter, we review our current understanding of these signaling pathways as they pertain to intoxication by Shiga toxins and ricin.

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Shiga toxins activate translational regulation pathways in intestinal epithelial cells

Cited by 26 publications

References 42 publications

Activation of the Classical Mitogen-Activated Protein Kinases Is Part of the Shiga Toxin-Induced Ribotoxic Stress Response and May Contribute to Shiga Toxin-Induced Inflammation

Activation of the Classical Mitogen-Activated Protein Kinases Is Part of the Shiga Toxin-Induced Ribotoxic Stress Response and May Contribute to Shiga Toxin-Induced Inflammation

Global Transcriptional Response of Macrophage-Like THP-1 Cells to Shiga Toxin Type 1

Ricin and Shiga Toxins: Effects on Host Cell Signal Transduction

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