The long term goal of these studies is to delineate the cellular and biochemical mechanisms by which tissue injury and infection lead to induction of biosynthesis of the rabbit acute phase plasma protein C-reactive Protein (CRP).
The specific aims of this proposal are to define the mechanisms by which activation of monocytes or macrophages induces increased synthesis of CRP in primary cultures of rabbit hepatocytes, and to compare these with the mechanisms leading to synthesis of the other major acute phase protein Serum Amyloid A protein (SAA). We will characterize the physiocochemical properties of the monokine (or monokines) responsible for induction of these proteins, with particular emphasis on whether the CRP-inducer and the SAA-inducer are identical. We will determine if hepatocyte CRP synthesis is induced by Interleukin-1 (as appears to be the case for murine SAA but not for all acute phase proteins). We will determine which rabbit cell types - blood monocytes, alveolar macrophages or Kupffer cells - are best capable of such induction, and whether unstimulated cells are as effective as in vitro stimulated cells. We will determine the effect of varying degrees of in vivo stimulation on the capacity of rabbit monocytic cells to induce acute phase protein synthesis in hepatocyte culture, and will delineate the time course of this phenomenon. We will investigate the cellular basis for the refractory state of CRP responsiveness produced by repeated intramuscular turpentine injection. We will determine whether biologic products expected to be present during the states which lead to acute phase protein production - materials of bacterial origin, tissue degradation products and local constituents of the inflammatory process - cause production in vitro of acute phase protein inducers upon addition to cultures of monocytic cells. We will investigate the possible roles of arachidonic acid metabolites, cyclic nucleotides, neurotransmitters and cytoskeletal elements in modulating the CRP response at the level of both the mononuclear cell and the hepatocyte. The serum concentrations of these proteins are markedly elevated in a number of acute and chronic inflammatory diseases, and following many forms of tissue injury. These studies bear on the basic biologic process of the organism's response to tissue injury and infection and are relevant to many diseases, including chronic autoimmune disorders. In addition, they are relevant to the pathogenesis of amyloidosis; SAA appears to be the precursor of secondary amyloid fibrils, and CRP bears close homology to SAP, a constituent of all types of amyloid tissue and a murine acute phase protein.
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