PMID: 9657756Jul 10, 1998Paper

Shiga toxin type 1 activates tumor necrosis factor-alpha gene transcription and nuclear translocation of the transcriptional activators nuclear factor-kappaB and activator protein-1.

Blood
R SakiriVernon L Tesh

Abstract

Shiga toxins (Stxs) produced by Shigella dysenteriae 1 and Escherichia coli have been implicated in the pathogenesis of bloody diarrhea, acute renal failure, and neurologic abnormalities. The pathologic hallmark of Stx-mediated tissue damage is the development of vascular lesions in which endothelial cells are swollen and detached from underlying basement membranes. However, in vitro studies using human vascular endothelial cells demonstrated minimal Stx-induced cytopathic effects, unless the target cells were also incubated with the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) or interleukin-1beta (IL-1bta). These cytokines have been shown to upregulate the expression of the Stx-binding membrane glycolipid globotriaosylceramide (Gb3). We show here that purified Stx1 induces TNF secretion by a human monocytic cell line, THP-1, in a dose- and time-dependent manner. Treatment of cells with both lipopolysaccharides (LPS) and Stx1 results in augmented TNF production. Treatment with the nontoxic Gb3-binding subunit of Stx1 or with an anti-Gb3 monoclonal antibody did not trigger TNF production. Northern blot analyses show that Stx1 causes increased TNF-alpha production through transcriptional activation. Increase...Continue Reading

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