Ribotoxic Stress Response to the Trichothecene Deoxynivalenol in the Macrophage Involves the Src Family Kinase Hck

Zhou, Hui Ren; Jia, Qunshan; Pestka, James J.

doi:10.1093/toxsci/kfi146

Cited by 113 publications

(75 citation statements)

References 69 publications

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“…Trichothecenes have immunoregulatory and cytotoxic effects on immune cells (28, 36, 49 -52). In addition, it has been concluded that these mycotoxins cause MAPK-mediated ribotoxic stress and apoptosis (53)(54)(55). We have previously shown in a mouse model of asthma that exposure to toxic S. chartarum induces lung inflammation characterized by the infiltration of immune cells, as well as the formation of granulomas and giant cells (32).…”

Section: Discussionmentioning

confidence: 99%

Trichothecene Mycotoxins Activate Inflammatory Response in Human Macrophages

Kankkunen

Rintahaka

Aalto

et al. 2009

The Journal of Immunology

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Damp building-related illnesses have caused concern for years in many countries. Although the problem is extensive, the knowledge of the immunological reactions behind damp building-related illnesses is still quite limited. Trichothecene mycotoxins form one major group of toxins, which possibly contribute to the illnesses. Stachybotrys chartarum is a well-known, but also controversial damp building mold and many strains of this mold are capable of producing trichothecenes. In this report, we have examined the effect of S. chartarum and trichothecene mycotoxins on the proinflammatory cytokine response in human macrophages. As a result, satratoxin-positive S. chartarum activated inflammasome-associated caspase-1, which is needed for proteolytic processing of IL-1β and IL-18. Furthermore, purified trichothecene mycotoxins, roridin A, verrucarin A, and T-2 toxin activated caspase-1, and these mycotoxins also strongly enhanced LPS-dependent secretion of IL-1β and IL-18. The satratoxin-positive strain of S. chartarum and the trichothecenes also triggered the activation of caspase-3, which is an effector caspase of apoptosis. Satratoxin-negative S. chartarum was not able to activate either caspase-1 or caspase-3. In conclusion, our results indicate that human macrophages sense trichothecene mycotoxins as a danger signal, which activates caspase-1, and further enables the secretion of IL-1β and IL-18 from the LPS-primed cells.

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Section: Discussionmentioning

confidence: 99%

Trichothecene Mycotoxins Activate Inflammatory Response in Human Macrophages

Kankkunen

Rintahaka

Aalto

et al. 2009

The Journal of Immunology

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“…ERK1/2, a MAPK, is activated both by trichothecenes such as DON via a process termed the 'ribotoxic stress response' and by the invasion of Salmonella Typhimurium in macrophages [29,39]. Recently, Yang et al [37] described that DON induces p21 mRNA stability in human epithelial cells in terms of interactions RNA-binding proteins via ERK 1/2 activation.…”

Section: Don Induced Cell Morphology Changesmentioning

confidence: 99%

“…However, many of their toxic effects might also be related to a rapidly ensuing dysregulation of intracellular cell signaling and consequent alterations in downstream gene expression [27]. Exposure to low levels of trichothecenes appears to promote expression of a diverse array of cytokines and proinflammatory genes in vitro and in vivo via a mechanism known as the ribotoxic stress response that involves multiple intracellular signaling cascades [26,38,39]. Trichothecenes such as DON are also known to rapidly activate mitogen-activated protein kinase (MAPK) via a process termed the ''ribotoxic stress response''.…”

Section: Introductionmentioning

confidence: 99%

The mycotoxin deoxynivalenol promotes uptake ofSalmonellaTyphimurium in porcine macrophages, associated with ERK1/2 induced cytoskeleton reorganization

Vandenbroucke¹,

Croubels²,

Verbrugghe³

et al. 2009

Vet. Res.

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-Both the mycotoxin deoxynivalenol (DON) and Salmonella Typhimurium are major issues in swine production. This study aimed at examining the interaction between DON and Salmonella Typhimurium at the level of the porcine innate immune system, represented by macrophages. First, we assessed the direct cytotoxic effect of DON on porcine macrophages. Incubation with 0.25 lg/mL of DON or higher resulted in a significant cytotoxic effect after 24 h of incubation. Secondly, the direct toxic effect of DON on the growth and on the expression of Salmonella pathogenicity island 1 (SPI-1) and SPI-2 virulence genes of Salmonella Typhimurium was determined. At low non-cytotoxic concentrations, as can be found in the serum of pigs, DON did not have any effect on either growth or virulence gene expression of Salmonella Typhimurium. However, when the invasion and intracellular survival of Salmonella Typhimurium in macrophages preexposed to 0.025 lg/mL of DON was examined, DON significantly promoted the uptake of Salmonella Typhimurium into macrophages. The enhanced uptake coincided with marked F-actin reorganization of the cells, which was due to the activation of extracellular signal-regulated protein kinase 1/2 (ERK1/2). These results suggest that low but relevant concentrations of DON modulate the innate immune system and could thus increase the susceptibility of pigs to infections with Salmonella Typhimurium.deoxynivalenol / Salmonella Typhimurium / pig / macrophage / cytoskeleton

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“…In addition, the toxin functions as an anti-apoptotic agent by increasing the survival of MCF-7 cell cultures undergoing apoptosis caused by serum withdrawal. On the other hand, the ribotoxic DON was found capable of inducing competing apoptotic (p38/p53/Bax/mitochondria/ caspase-3) and survival (ERK/AKT/p90Rsk/Bad) signaling pathways in macrophages (Zhou et al 2005). Because of their mode of action, microRNAs (miRNAs or miRs), members of the RNA interference (RNAi) system, seem particularly suitable for studying the molecular processes underlying pathological alterations of cells and tissues at the gene and protein levels (Hudder and Novak 2008).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA expression profiles in liver and colon of sexually immature gilts after exposure to Fusarium mycotoxins

Brzuzan¹,

Woźny²,

Wolińska-Nizioł³

et al. 2015

Polish Journal of Veterinary Sciences

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To improve our knowledge of the role of microRNAs (miRs) in responses of the porcine digestive system to two Fusarium mycotoxins, zearalenone (ZEN) and deoxynivalenol (DON), we examined the expression of 7 miRs (miR-9, miR-15a, miR-21, miR-34a, miR-122, miR-125b, and miR-192), previously found to be deregulated in diseased liver and colon cells. In this study, immature gilts were exposed to NOEL doses of ZEN (40 μg/kg/d), DON (12 μg/kg/d), ZEN+DON (40+12 μg/kg/d), and placebo (negative control group) for 7, 14, 21, 28, 35, and 42 days. Before the treatment, expression levels of the selected miRs were measured in the liver, the duodenum, the jejunum, and the ascending and the descending colon of the gilts. Hierarchical clustering of the tissues by their miR expression profiles was consistent with what would be expected based on the anatomical locations and the physiological functions of the organs, suggesting that functions of the miRs are related to the specificities of the tissues in which they are expressed. A subset of 2 pairs of miRs (miR-21+miR-192 and miR-15a+miR-34a), which were assigned to two distinct clusters based on their tissue abundance, was then evaluated in the liver and the ascending and the descending colon during the treatment. The most meaningful results were obtained from the ascending colon, where a significant effect of the treatment was observed, suggesting that during the exposure to mycotoxins, the pathways involved in cell proliferation and survival were disordered. Changes in miR expression in the liver and the descending colon of the treated gilts were smaller, and were associated more with treatment duration than the exposure to ZEN, DON, or ZEN+DON. Further research should focus on identification of genes whose expression is regulated by these aberrantly expressed miRs. This should facilitate understanding of the miRNA-regulated biological effects of mycotoxins.

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Ribotoxic Stress Response to the Trichothecene Deoxynivalenol in the Macrophage Involves the Src Family Kinase Hck

Cited by 113 publications

References 69 publications

Trichothecene Mycotoxins Activate Inflammatory Response in Human Macrophages

Trichothecene Mycotoxins Activate Inflammatory Response in Human Macrophages

The mycotoxin deoxynivalenol promotes uptake ofSalmonellaTyphimurium in porcine macrophages, associated with ERK1/2 induced cytoskeleton reorganization

MicroRNA expression profiles in liver and colon of sexually immature gilts after exposure to Fusarium mycotoxins

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