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-α, or IL-1β, 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-α 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-κB 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.

Orthopedic surgery increases atherosclerotic lesions and necrotic core area in ApoE−/− mice

“…The surgical procedure caused a marked acute systemic inflammatory response as demonstrated by a rapid increase in SAA, a relatively stable inflammation marker that integrates the signals of proatherogenic cytokines (IL1, TNFα, IL6), many of which may have contributed to the effect on the atherosclerotic leasion 16,17 . Several studies suggest that SAA itself participates in the pathogenesis of atherosclerosis and a recent study shows that it may contribute to plaque vulnerability 18 .…”

Serum Amyloid A Is an Endogenous Ligand That Differentially Induces IL-12 and IL-23

“…A recent study using a SAA1-driven luciferase transgene demonstrates that SAA expression in hepatocytes could be induced within 4 h after LPS stimulation (64), indicating that SAA is an early signal generated by the invading microbes. Our results show that SAA is able to stimulate IL-23 production at a relatively low concentration of 1 M, which is a fraction of its peak plasma concentration.…”

Denervation protects limbs from inflammatory arthritis via an impact on the microvasculature

“…2A) revealed that most of the differential expression on day 4 after serum administration carried over from the prechallenged state (day 0). Few immunity-or inflammation-related genes made the twofold cutoff, notably the gene encoding SAA-1 did, an acute-phase reactant whose levels mount in blood and synovial fluid of arthritic humans and rodents (13) (Tables S5 and S6). …”