Role of tumor necrosis factor and nitric oxide in the cytotoxic effects of Clostridium difficile toxin A and toxin B on macrophages

Filho, Antônio Aldo Melo; Souza, Marcellus H.; Lyerly, David M.; Cunha, Fernando; Lima, Aldo A. M.; Ribeiro, Ronaldo A.

doi:10.1016/s0041-0101(96)00172-9

Cited by 27 publications

(12 citation statements)

References 34 publications

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“…Previous studies have shown that murine peritoneal macrophages produce TNF-α after exposure to TcdA or TcdB [32]. Here, we have found that a murine macrophage cell line RAW 264.7 produced copious amount of TNF-α after treatments with either TcdA or TcdB.…”

Section: Resultsmentioning

confidence: 53%

“…One of the most important cytokine mediators released by macrophages is TNF-α, which is a central mediator of inflammation and plays a critical role in host response to infection and tissue injury [48]. However, only a few reports documented C. difficile toxin-induced TNF-α production in murine peritoneal macrophages [32-34]. The underlying mechanism of the induction of TNF-α by C. difficile toxins however has not been investigated.…”

Section: Discussionmentioning

confidence: 99%

“…Of these mediators, TNF-α is one of the central mediators of inflammation and plays a critical role in host response to infection and cell injury [31]. Only a few reports documented TNF-α production by murine peritoneal macrophages in response to TcdA or TcdB treatments [32-34]. In the present study, we used RAW 264.7 macrophages to dissect the role of TcdA in the induction of TNF-α.…”

Section: Introductionmentioning

confidence: 99%

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Essential role of the glucosyltransferase activity in Clostridium difficile toxin-induced secretion of TNF-α by macrophages

Sun

Tzipori

et al. 2009

Microbial Pathogenesis

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Clostridium difficile causes serious and potentially fatal inflammatory diseases of the colon. Two large protein toxins, TcdA and TcdB, have been clearly implicated in pathogenesis. The goal of this study was to determine whether the glucosyltransferase activity of the toxins is critical for the induction of tumor necrosis factor-α (TNF-α), an important cytokine mediating both local and systematic inflammatory response. A dose-dependent TNF-α secretion was demonstrated in murine macrophage cell line RAW 264.7 after exposure to TcdA or TcdB. TNF-α production was blocked by anti-toxin antibodies, indicating that the cytokine-driven response is mediated by the toxins. Both toxins disrupted the cytoskeleton of host cells, while cytoskeleton disruptions using cytochalasin D and latrunculin B did not affect TNF-α production. The TNF-α synthesis was inhibited by reagents that target clathrin-dependent endocytosis or prevent endosomal acidification, suggesting that the endocytosis pathway is necessary for the induction of TNF-α. Furthermore, knockout of the enzymatic activity by mutating two key amino acids in the catalytic domain of TcdA abolished its cytokine-inducing activity. Our studies demonstrated a crucial role of the glucosyltransferase activity of C. difficile toxins in the induction of TNF-α in macrophages.

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Section: Resultsmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Essential role of the glucosyltransferase activity in Clostridium difficile toxin-induced secretion of TNF-α by macrophages

Sun

Tzipori

et al. 2009

Microbial Pathogenesis

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“…The role of NO on TxA-induced damage still is ambiguous. Melo Filho and coworkers reported that TxA and TxB did not induce the production of NO by macrophages in vitro, and that the use of an inhibitor of NOS (L-NIO) did not modify the cellular damage induced by these toxins (37). On the other hand, TxB has been shown to promote the increased expression of NOS2 by inactivating the G protein of the Rho family (22,38).…”

Section: Discussionmentioning

confidence: 99%

Adenosine Deaminase Inhibition PreventsClostridium difficileToxin A-Induced Enteritis in Mice

et al. 2011

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“…Following detachment, intestinal epithelial cells can be driven to produce IL-8 and up-regulate ICAM-17 leading to the neutrophil chemoattraction, adhesion and subsequent mucosal inflammation8. The disruption of the mucosal barrier allows toxins to activate the immune cells within the lamina propria and to trigger the production of IL-8, IL-1β, TNF and nitric oxide (NO)7–10. These events can lead to further immune cell infiltrate and the tissue damage associated with C.difficile -associated disease (CDAD).…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-Inducible Factor Signaling Provides Protection in Clostridium difficile-Induced Intestinal Injury

Hirota

Fines

et al. 2010

Gastroenterology

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Background & Aims Clostridium difficile (C.difficile) is the leading cause of nosocomial infectious diarrhea. Increasing incidence, antibiotic resistance and more virulent strains have dramatically increased the number of C.difficile-related deaths worldwide. The innate host response mechanisms to C.difficile are not resolved; however, we hypothesize that hypoxia-inducible factor (HIF-1) plays an innate protective role in C.difficile colitis. Thus, we assessed the impact of C.difficile toxins on the regulation of HIF-1 and evaluated the role of HIF-1α in C.difficile-mediated injury/inflammation. Methods In vitro studies assessed HIF-1α mRNA, protein levels and DNA binding events in human mucosal biopsies and Caco-2 cells exposed to C.difficile toxins. In vivo studies employed the murine ileal loop model of C.difficile toxin-induced intestinal injury. Mice with targeted deletion of HIF-1α in the intestinal epithelium were used to assess the impact of HIF-1α signaling in response to C.difficile toxin. Results Mucosal biopsies and Caco-2 cells exposed to C.difficile toxin displayed a significant increase in HIF-1α transcription and protein levels. Toxin-induced DNA binding was also observed in Caco-2 cells. Toxin-induced HIF-1α accumulation was attenuated by nitric oxide synthase inhibitors. In vivo, deletion of intestinal epithelial HIF-1α resulted in more severe toxin-induced intestinal injury and inflammation. In contrast, stabilization of HIF-1α, with dimethyloxallyl glycine, attenuated toxin-induced injury and inflammation. This was associated with an induction of HIF-1-regulated protective factors including VEGFa, CD73 and intestinal trefoil factor and down-regulation of proinflammatory molecules TNF and KC. Conclusions Our study is the first to describe the innate protective role for HIF-1α in response to C.difficile toxins. Harnessing the innate protective actions of HIF-1α in response to C.difficile toxins may represent a novel form of therapy for C.difficile-associated disease.

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Role of tumor necrosis factor and nitric oxide in the cytotoxic effects of Clostridium difficile toxin A and toxin B on macrophages

Cited by 27 publications

References 34 publications

Essential role of the glucosyltransferase activity in Clostridium difficile toxin-induced secretion of TNF-α by macrophages

Essential role of the glucosyltransferase activity in Clostridium difficile toxin-induced secretion of TNF-α by macrophages

Adenosine Deaminase Inhibition PreventsClostridium difficileToxin A-Induced Enteritis in Mice

Hypoxia-Inducible Factor Signaling Provides Protection in Clostridium difficile-Induced Intestinal Injury

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