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Major acute-phase reactant synthesis during chronic inflammation in amyloid-susceptible and -resistant mouse strains
K Zahedi1, W A Gonnerman, F C Debeer
1Division of Immunology, Children's Hospital, Boston, Massachusetts.
Abstract:
Hepatic levels of mRNA specific for total serum amyloid A (SAA), the SAA1 and SAA2 isotypes, serum amyloid P (SAP), C-reactive protein (CRP), and fibronectin, as well as the plasma concentrations of SAA and SAP were examined in amyloid-resistant (A/J) and amyloid-susceptible (CBA/J) mice during azocasein-induced chronic inflammation. In both strains hepatic SAA and SAP mRNA levels and plasma SAA and SAP protein concentrations increased dramatically during the early stages of inflammation; this was followed by a decrease to concentrations that were maintained at levels considerably higher than background. The ratios of SAA1 and SAA2 mRNA and plasma protein were 1:1 throughout. This indicated that there was no preferential accumulation of mRNA specifying a particular isotype and no preferential synthesis or clearance of a particular isotype during chronic inflammation and the early stages of amyloidogenesis in either strain. Similarly, hepatic SAP mRNA levels in both strains increased dramatically during the early stages of inflammation and were subsequently maintained at elevated levels. Plasma SAP concentrations increased rapidly during the first three days of the study in both A/J and CBA/J mice; however, during the later stages of inflammation, A/J plasma SAP levels decreased to a steady-state concentration that was approximately half that observed in CBA/J mice. Our results identify differences in the hepatic mRNA and plasma protein levels of the major mouse acute-phase reactants (APR) in the amyloid-resistant A/J and amyloid-susceptible CBA/J mouse strains. These findings are consistent with circulating inflammatory APR concentrations contributing, together with other factors, to the onset and pathogenesis of secondary amyloidosis.
Insights
Mice with different amyloidosis susceptibilities show similar early inflammatory responses but distinct later-stage protein levels. These findings suggest circulating inflammatory acute-phase reactants contribute to secondary amyloidosis pathogenesis.
Area of Science:
- Immunology
- Biochemistry
- Pathology
Background:
- Secondary amyloidosis is a complex disease.
- Acute-phase reactants (APRs) play a role in inflammation and disease pathogenesis.
- Understanding APR dynamics in different genetic backgrounds is crucial.
Purpose of the Study:
- To compare hepatic mRNA and plasma protein levels of key APRs in amyloid-resistant (A/J) and amyloid-susceptible (CBA/J) mice during chronic inflammation.
- To investigate the role of APRs in the early stages of amyloidogenesis.
Main Methods:
- Azocasein-induced chronic inflammation model in A/J and CBA/J mice.
- Quantification of hepatic mRNA for serum amyloid A (SAA), SAA1, SAA2, serum amyloid P (SAP), C-reactive protein (CRP), and fibronectin.
- Measurement of plasma SAA and SAP protein concentrations.
Main Results:
- Both mouse strains exhibited dramatically increased hepatic SAA and SAP mRNA and plasma SAA and SAP during early inflammation, maintained at elevated levels.
- SAA1 and SAA2 mRNA and protein ratios remained 1:1, indicating no isotype preference.
- While both strains showed increased plasma SAP, A/J mice had significantly lower levels than CBA/J mice in later stages.
Conclusions:
- Hepatic and plasma APR levels differ between amyloid-resistant and susceptible mouse strains.
- These differences in circulating APRs may contribute to the development and pathogenesis of secondary amyloidosis.