title: Role of apoptotic signaling pathways in regulation of inflammatory responses to ricin in primary murine macrophages.
abstract: Because of its lethal effects, ease of preparation, and ability to be delivered by aerosolization, ricin has been developed as a lethal weapon by various terrorist groups. When introduced into the pulmonary system of rodents, ricin causes pathological changes in the lung that are known to occur in acute respiratory distress syndrome (ARDS). Early response cytokines such as TNF-alpha and IL-1 are known to play a critical role in the pathogenesis of ARDS. Ricin induces the release of these pro-inflammatory cytokines and the transcriptional activation of the genes that encode them in vitro and in vivo. Macrophages, considered to act as upstream regulators of inflammatory cascades, may play a central role in the pathogenesis and the development of ricin-induced ARDS because of their ability to make and secrete pro-inflammatory cytokines. Exposure of primary macrophages to ricin in vitro led to activation of stress-activated protein kinases, increased expression of pro-inflammatory mRNA transcripts, subsequent increase in the synthesis and secretion of TNF-alpha, and apoptotic cell death. Interestingly, macrophages required the engagement of the apoptotic cascade for the maximal synthesis and release of some pro-inflammatory mediators. This work identifies a cross talk between the apoptotic and inflammatory signaling pathways induced by ricin in primary macrophages.
authors.affiliation: Department of Cell and Developmental Biology, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR, USA.
authors.forename: Veselina
authors.initials: V
authors.lastname: Korcheva
authors.forename: John
authors.initials: J
authors.lastname: Wong
authors.forename: Meghan
authors.initials: M
authors.lastname: Lindauer
authors.forename: David B
authors.initials: DB
authors.lastname: Jacoby
authors.forename: Mihail S
authors.initials: MS
authors.lastname: Iordanov
authors.forename: Bruce
authors.initials: B
authors.lastname: Magun
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D012128:Respiratory Distress Syndrome / Q000139:chemically induced* / Q000235:genetics / Q000276:immunology*; D012276:Ricin / Q000494:pharmacology / Q000506:poisoning*; D015398:Signal Transduction
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; C476093:z-Val-Ala-Asp(Ome)-fluoromethylketone; D012276:Ricin; D020928:Mitogen-Activated Protein Kinases; D020169:Caspases