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