Down-regulation of the major circulating precursors of proteins deposited in secondary amyloidosis by a recombinant mouse interleukin-1 receptor antagonist.

An inflammatory response was induced in C57BL/6 mice using silver nitrate. Co-administration of a recombinant mouse interleukin-1 receptor antagonist (rmIL-1ra) significantly reduced the magnitude of hepatic induction of the mRNA specifying the serum amyloid A (A-SAA) isoforms A-SAA1 and A-SAA2 for up to 24 h. In relative terms, the amount by which the induction of serum A-SAA protein levels could be countered by the antagonist was less, probably reflecting extrahepatic A-SAA synthesis that is regulated independently of IL-1. Induction of hepatic serum amyloid P component (SAP) mRNA and other acute-phase reactant (APR) mRNA were all partially blocked by rmIL-1ra for up to 24 h, indicating that induction of these APR mRNA involves both IL-1 and additional factors acting independently of IL-1. Hepatic mRNA levels of the negative APR apolipoprotein A-I (apo A-I) and serum albumin were down-regulated by silver nitrate treatment; rmIL-1ra partially restored serum albumin mRNA levels but not those of apo A-I. The IL-1ra-mediated reduction in inflammation-induced hepatic mRNA and serum protein concentrations of A-SAA and SAP (the precursors of the main protein components of amyloid deposits in secondary amyloidosis) was, however, not sufficient to prevent or delay early amyloid deposition in the silver nitrate/amyloid enhancing factor model of accelerated amyloidosis. The rmIL-1ra may be a useful component in future therapies to control inflammation and secondary amyloidosis; in addition, it will be a useful tool for the detailed analysis of the IL-1-driven aspects of inflammation per se.