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This Article Full Text Full Text (PDF) All Versions of this Article: 293/6/L1385    most recent 00207.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Wong, J. Articles by Magun, B. E. Search for Related Content PubMed PubMed Citation Articles by Wong, J. Articles by Magun, B. E.

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

¹Department of Cell and Developmental Biology and ²Division of Pulmonary and Critical Care Medicine, Oregon Health and Science University, Portland, Oregon

Submitted 22 May 2007 ; accepted in final form 10 September 2007

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-B 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-B as one of the transcription factors whose binding sites were overrepresented. Although airway cells secrete TNF- in response to ricin, blocking TNF- did not prevent ricin-induced activation of NF-B. Decreased levels of IB- in airway cells exposed to ricin suggest that translational suppression may be responsible for the activation of NF-B. Inhibition of p38 MAPK by a chemical inhibitor or NF-B 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-B pathways are potential therapeutic targets for reducing the inflammatory consequences of ricin poisoning.

lung; airway epithelium; inflammation; tumor necrosis factor-; p38 mitogen-activated protein kinase; nuclear factor-B