Anthrax Lethal Toxin Enhances IκB Kinase Activation and Differentially Regulates Pro-inflammatory Genes in Human Endothelium

Warfel, Jason M.; D’Agnillo, Felice

doi:10.1074/jbc.m109.036970

Cited by 8 publications

(8 citation statements)

References 72 publications

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“…Control and LT-treated cells showed similar baseline levels of ubiquitinated proteins and exhibited similar increases in ubiquitinated proteins in response to MG132. These data are consistent with our previous finding that LT does not enhance or repress proteosome activity in human endothelial cells [32].…”

Section: Resultssupporting

confidence: 94%

Anthrax Lethal Toxin Downregulates Claudin-5 Expression in Human Endothelial Tight Junctions

et al. 2013

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Vascular leakage pathologies such as pleural effusion and hemorrhage are hallmarks of anthrax pathogenesis. We previously reported that anthrax lethal toxin (LT), the major virulence factor of anthrax, reduces barrier function in cultured primary human microvascular endothelial cells. Here, we show that LT-induced barrier dysfunction is accompanied by the reduced expression of the endothelial tight junction (TJ) protein claudin-5 but no change in the expression of other TJ components occludin, ZO-1, ZO-2, or the adherens junction (AJ) protein VE-cadherin. The downregulation of claudin-5 correlated temporally and dose-dependently with the reduction of transendothelial electrical resistance. LT-induced loss of claudin-5 was independent of cell death and preceded the appearance of actin stress fibers and altered AJ morphology. Pharmacological inhibition of MEK-1/2, two kinases that are proteolytically inactivated by LT, showed a similar reduction in claudin-5 expression. We found that LT reduced claudin-5 mRNA levels but did not accelerate the rate of claudin-5 degradation. Mice challenged with LT also showed significant reduction in claudin-5 expression. Together, these findings support a possible role for LT disruption of endothelial TJs in the vascular leakage pathologies of anthrax.

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Section: Resultssupporting

confidence: 94%

Anthrax Lethal Toxin Downregulates Claudin-5 Expression in Human Endothelial Tight Junctions

et al. 2013

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“…There is no information in the literature about the cytokine milieu provoked by anthrax Sterne-strain vaccine in cattle, which may explain this isotype-profiling. However, there are reports supporting the induction of pro-inflammatory cytokines during murine anthrax [29] and by anthrax lethal toxin in human endothelium [30], meaning that this bacterium can promote a Th1-biased pro-inflammatory environment. Is it possible that the cytokine environment generated by the anthrax vaccine promoted an expansion of Th1 clones which in term helped to induce the proliferation of IgG2-producing B cells.…”

Section: Discussionmentioning

confidence: 98%

Simultaneous immunization of cattle with foot-and-mouth disease (FMD) and live anthrax vaccines do not interfere with FMD booster responses

Trotta¹,

Lahore

Cardoso³

et al. 2015

Trials in Vaccinology

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a b s t r a c tFoot-and-mouth disease (FMD) vaccination in Argentina is compulsory for most of the cattle population and conducted by certified veterinarians. This organized campaign may facilitate the controlled application of other vaccines against endemic diseases, provided immune responses against FMD are not hindered. There is no published information on the interference of immunity against FMD vaccines when applied together with a live bacterial vaccine. In this study we evaluated if the simultaneous application of a Bacillus anthracis live vaccine with a commercial tetravalent oil-based FMD vaccine (FMD-vac) used in Argentina, modifies the antibody booster responses against FMD virus (FMDV) in cattle. Two groups of 16 heifers with comparable liquid phase blocking ELISA (LPBE) titers were immunized with the FMD-vac alone or simultaneously with a commercial attenuated bovine anthrax Sterne strain vaccine (ABV). Serum samples were obtained at 0, 25, 60 and 90 days post vaccination (dpv) and specific antibodies against two FMDV vaccine strains were assessed by LPBE, avidity and IgG-isotype ELISAs. Bovines immunized with FMD-vac or FMDV-V + ABV responded with a boost in the LPBE antibody titers and avidity at 25 dpv, and remained within similar levels up to the end of the study. Animals vaccinated with FMD-vac + ABV had significantly higher LPBE titers at 25 dpv, compared to those immunized with FMD-vac alone; which was due to an increase in IgG2 titers. Overall, antibody titers elicited in both groups were similar and followed comparable kinetics over time. We conclude that the simultaneous application of a live anthrax vaccine with the current FMD tetravalent vaccine used in Argentina in cattle previously immunized against FMD, did not counteract the serological response induced by FMD vaccination.

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“…HAEC also upregulate CCL-2 (MCP-1), E-selectin, and IL-8 in response to LPS (61). However, both NF-B and AP-1 pathways upregulate CCL-2 (70). Regulation of CCL-2 secretion by endothelium through NF-B-and AP-1-mediated pathways is affected by such diverse stimuli as LPS, TNF-␣, anthrax toxin (70), and activated platelet interactions (14).…”

Section: Discussionmentioning

confidence: 99%

“…However, both NF-B and AP-1 pathways upregulate CCL-2 (70). Regulation of CCL-2 secretion by endothelium through NF-B-and AP-1-mediated pathways is affected by such diverse stimuli as LPS, TNF-␣, anthrax toxin (70), and activated platelet interactions (14). Our data suggest a similar synergistic effect on CCL-2 secretion in APM-treated endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Comparative gene responses to collected ambient particles in vitro: endothelial responses

Aung

Lamé²,

Gohil³

et al. 2011

Physiological Genomics

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Epidemiologic studies associate exposure to ambient particulate matter (APM) with increased cardiovascular mortality. Since both pulmonary inflammation and systemic circulation of ultrafine particles are hypothesized as initiating cardiovascular effects, we examined responses of potential target cells in vitro. Human aortic endothelial cells (HAEC) were exposed to 10 μg/ml fine and ultrafine APM collected in an urban setting in summer 2006 or winter 2007 in the San Joaquin Valley, California. RNA isolated after 3 h was analyzed with high-density oligonucleotide arrays. Summer APM treatment affected genes involved in xenobiotic and oxidoreductase activity, transcription factors, and inflammatory responses in HAEC, while winter APM had a robust xenobiotic but lesser inflammatory response. Real-time polymerase chain reaction analysis confirmed that particulate matter (PM)-treated HAEC increased mRNA levels of xenobiotic response enzymes CYP1A1, ALDH1A3, and TIPARP and cellular stress response transcription factor ATF3. Inflammatory response genes included E-selectin, PTGS2, CXCL-2 (MIP-2α), and CCL-2 (MCP-1). Multiplex protein assays showed secretion of IL-6 and MCP-1 by HAEC. Since induction of CYP1A1 is mediated through the ligand-activated aryl hydrocarbon receptor (AhR), we demonstrated APM induced AhR nuclear translocation by immunofluorescence and Western blotting and activation of the AhR response element using a luciferase reporter construct. Inhibitor studies suggest differential influences of polycyclic aromatic hydrocarbon signaling, ROS-mediated responses and endotoxin alter stress and proinflammatory endothelial cell responses. Our findings demonstrate gene responses correlated with current concepts that systemic inflammation drives cardiovascular effects of particulate air pollution. We also demonstrate a unique pattern of gene responses related to xenobiotic metabolism in PM-exposed HAEC.

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Anthrax Lethal Toxin Enhances IκB Kinase Activation and Differentially Regulates Pro-inflammatory Genes in Human Endothelium

Cited by 8 publications

References 72 publications

Anthrax Lethal Toxin Downregulates Claudin-5 Expression in Human Endothelial Tight Junctions

Anthrax Lethal Toxin Downregulates Claudin-5 Expression in Human Endothelial Tight Junctions

Simultaneous immunization of cattle with foot-and-mouth disease (FMD) and live anthrax vaccines do not interfere with FMD booster responses

Comparative gene responses to collected ambient particles in vitro: endothelial responses

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