MECHANISM OF SERUM AMYLOID A PROTEIN SYNTHESIS

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Serum amyloid A (SAA) is associated with reactive amyloidosis that occurs as a consequence of chronic infection and inflammatory diseases such as rheumatoid arthritis, granulomatous bowel disease or osteomyelitis. It is also associated with Familial Mediterranean Fever (FMF) and occasionally in asymptomatic individuals with FMF kindreds. In reactive amyloidosis, deposition of amyloid fibrils composed of protein AA, a degradative product of the polymorphic serum amyloid A protein, can occur in multiple organs resulting in their dysfunction. Although the etiology or pathogenic mechanisms of this process is incompletely understood, increased biosynthesis of the involved protein, SAA, under chronic inflammatory condition is quite evident. A cascade of molecular events involving cytokines released during the inflammatory processes like chronic infection and rheumatoid arthritis, trigger the overexpression of SAA, the precursor of amyloid fibrils found in tissues affected by secondary or reactive amyloidosis.. Understanding the activation mechanism of the dysregulated SAA expression may provide useful information on the pathogenesis of the SAA-linked disease. It is hypothesized that increased expression of SAA gene induced by the factors activated during chronic inflammation is a major molecular event that triggers the observed pathogenic condition. To elucidate the molecular events responsible for the overexpression of SAA in chronic inflammatory condition, we intend to pursue the following objectives: 1) characterization of SIF, a novel cytokine-inducible inflammatory factor, 2) role of different inflammatory cytokines on SAA expression in extra-hepatic cells 3) expression pattern of SIF under acute and chronic conditions, 4) interaction of the IL-1 induced nuclear factor with SIF, and 5) structural analysis of SIF. Identification and characterization of cellular factors and their interaction with cis-acting elements of SAA gene will be studied by the gel mobility shift assay, competition analyses, use of inhibitors, cotransfection analysis and site- directed mutagenesis. The major contribution that this study can make is an understanding of the basic mechanisms of response to inflammation. These studies can lead to the design of treatments to reduce the effects of chronic inflammation and increase the rate of recovery from tissue damage.