title: Serum amyloid A-luciferase transgenic mice: response to sepsis, acute arthritis, and contact hypersensitivity and the effects of proteasome inhibition.
abstract: Acute phase serum amyloid A proteins (A-SAAs) are multifunctional apolipoproteins produced in large amounts during the acute phase of an inflammation and also during the development of chronic inflammatory diseases. In this study we present a Saa1-luc transgenic mouse model in which SAA1 gene expression can be monitored by measuring luciferase activity using a noninvasive imaging system. When challenged with LPS, TNF-alpha, or IL-1beta, in vivo imaging of Saa1-luc mice showed a 1000- to 3000-fold induction of luciferase activity in the hepatic region that peaked 4-7 h after treatment. The induction of liver luciferase expression was consistent with an increase in SAA1 mRNA in the liver and a dramatic elevation of the serum SAA1 concentration. Ex vivo analyses revealed luciferase induction in many tissues, ranging from several-fold (brain) to >5000-fold (liver) after LPS or TNF-alpha treatment. Pretreatment of mice with the proteasome inhibitor bortezomib significantly suppressed LPS-induced SAA1 expression. These results suggested that proteasome inhibition, perhaps through the NF-kappaB signaling pathway, may regulate SAA1 expression. During the development of acute arthritis triggered by intra-articular administration of zymosan, SAA1 expression was induced both locally at the knee joint and systemically in the liver, and the induction was significantly suppressed by bortezomib. Induction of SAA1 expression was also demonstrated during contact hypersensitivity induced by topical application of oxazolone. These results suggest that both local and systemic induction of A-SAA occur during inflammation and may contribute to the pathogenesis of chronic inflammatory diseases associated with amyloid deposition.
authors.affiliation: Xenogen, Alameda, CA 94501, USA. ning.zhang@xenogen.com
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.forename: Muhammad H
authors.initials: MH
authors.lastname: Ahsan
authors.forename: Anthony F
authors.initials: AF
authors.lastname: Purchio
authors.forename: David B
authors.initials: DB
authors.lastname: West
mesh_terms: D000208:Acute Disease; D000818:Animals; D001169:Arthritis, Experimental / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D001897:Boronic Acids / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000069286:Bortezomib; D003877:Dermatitis, Contact / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D004790:Enzyme Induction / Q000187:drug effects / Q000235:genetics; D005260:Female; D005822:Genetic Vectors; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008156:Luciferases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009928:Organ Specificity / Q000187:drug effects / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D018805:Sepsis / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D000685:Serum Amyloid A Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D001897:Boronic Acids; D008070:Lipopolysaccharides; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000685:Serum Amyloid A Protein; D014409:Tumor Necrosis Factor-alpha; D000069286:Bortezomib; D008156:Luciferases; D046988:Proteasome Endopeptidase Complex