Proinflammatory responses of human airway cells to ricin involve stress-activated protein kinases and NF-κB

John Wong, Veselina Korcheva, David Jacoby, Bruce E. Magun

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Ricin is a potential bioweapon because of its toxicity, availability, and ease of production. When delivered to the lungs, ricin causes severe pulmonary damage with symptoms that are similar to those observed in acute lung injury and adult respiratory distress syndrome. The airway epithelium plays an important role in the pathogenesis of many lung diseases, but its role in ricin intoxication has not been elucidated. Exposure of cultured primary human airway epithelial cells to ricin resulted in the activation of SAPKs and NF-κB and in the increased expression of multiple proinflammatory molecules. Among the genes upregulated by ricin and identified by microarray analysis were those associated with transcription, nucleosome assembly, inflammation, and response to stress. Sequence analysis of the promoters of these genes identified NF-κB as one of the transcription factors whose binding sites were overrepresented. Although airway cells secrete TNF-α in response to ricin, blocking TNF-α did not prevent ricin-induced activation of NF-κB. Decreased levels of IκB-α in airway cells exposed to ricin suggest that translational suppression may be responsible for the activation of NF-κB. Inhibition of p38 MAPK by a chemical inhibitor or NF-κB by short interfering RNA resulted in a marked reduction in the expression of proinflammatory genes, demonstrating the importance of these two pathways in ricin intoxication. Therefore, the p38 MAPK and NF-κB pathways are potential therapeutic targets for reducing the inflammatory consequences of ricin poisoning.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume293
Issue number6
DOIs
StatePublished - Dec 2007

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Ricin
Proto-Oncogene Proteins c-akt
Heat-Shock Proteins
p38 Mitogen-Activated Protein Kinases
Lung
Nucleosomes
Acute Lung Injury
Adult Respiratory Distress Syndrome
Microarray Analysis
Poisoning
Small Interfering RNA
Lung Diseases
Genes
Sequence Analysis
Transcription Factors
Epithelium
Epithelial Cells
Binding Sites
Inflammation
Gene Expression

Keywords

  • Airway epithelium
  • Inflammation
  • Lung
  • Nuclear factor-κB
  • Tumor necrosis factor-α; p38 mitogen-activated protein kinase

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Cell Biology
  • Physiology

Cite this

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title = "Proinflammatory responses of human airway cells to ricin involve stress-activated protein kinases and NF-κB",
abstract = "Ricin is a potential bioweapon because of its toxicity, availability, and ease of production. When delivered to the lungs, ricin causes severe pulmonary damage with symptoms that are similar to those observed in acute lung injury and adult respiratory distress syndrome. The airway epithelium plays an important role in the pathogenesis of many lung diseases, but its role in ricin intoxication has not been elucidated. Exposure of cultured primary human airway epithelial cells to ricin resulted in the activation of SAPKs and NF-κB and in the increased expression of multiple proinflammatory molecules. Among the genes upregulated by ricin and identified by microarray analysis were those associated with transcription, nucleosome assembly, inflammation, and response to stress. Sequence analysis of the promoters of these genes identified NF-κB as one of the transcription factors whose binding sites were overrepresented. Although airway cells secrete TNF-α in response to ricin, blocking TNF-α did not prevent ricin-induced activation of NF-κB. Decreased levels of IκB-α in airway cells exposed to ricin suggest that translational suppression may be responsible for the activation of NF-κB. Inhibition of p38 MAPK by a chemical inhibitor or NF-κB by short interfering RNA resulted in a marked reduction in the expression of proinflammatory genes, demonstrating the importance of these two pathways in ricin intoxication. Therefore, the p38 MAPK and NF-κB pathways are potential therapeutic targets for reducing the inflammatory consequences of ricin poisoning.",
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AU - Korcheva, Veselina

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AB - Ricin is a potential bioweapon because of its toxicity, availability, and ease of production. When delivered to the lungs, ricin causes severe pulmonary damage with symptoms that are similar to those observed in acute lung injury and adult respiratory distress syndrome. The airway epithelium plays an important role in the pathogenesis of many lung diseases, but its role in ricin intoxication has not been elucidated. Exposure of cultured primary human airway epithelial cells to ricin resulted in the activation of SAPKs and NF-κB and in the increased expression of multiple proinflammatory molecules. Among the genes upregulated by ricin and identified by microarray analysis were those associated with transcription, nucleosome assembly, inflammation, and response to stress. Sequence analysis of the promoters of these genes identified NF-κB as one of the transcription factors whose binding sites were overrepresented. Although airway cells secrete TNF-α in response to ricin, blocking TNF-α did not prevent ricin-induced activation of NF-κB. Decreased levels of IκB-α in airway cells exposed to ricin suggest that translational suppression may be responsible for the activation of NF-κB. Inhibition of p38 MAPK by a chemical inhibitor or NF-κB by short interfering RNA resulted in a marked reduction in the expression of proinflammatory genes, demonstrating the importance of these two pathways in ricin intoxication. Therefore, the p38 MAPK and NF-κB pathways are potential therapeutic targets for reducing the inflammatory consequences of ricin poisoning.

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