Date of Award

1987

Degree Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Medical Sciences

Supervisor

Dr. Jack Gauldie

Abstract

The acute phase response in mammals to tissue injury or infection is characterized by a number of systemic effects including fever, neutrophilia and increases in serum levels of liver-derived (synthesized by hepatocytes) acute phase proteins. Soluble mediators or cytokines released by cells of the monocyte/macrophage lineage have been implicated in the initiation of the increased synthesis of protein by hepatocytes and include Hepatocyte Stimulating Factor (HSF) and Interleukin-1 (IL-l). The nature of HSF and IL-1 and their activities in inducing acute phase protein synthesis in vitro by primary cultures of rat hepatocytes and by human Hep-G2 cells was examined. Human peripheral blood monoocyte (PBM) -derived HSF showed different characteristics than IL-1 upon separation by chromatography and gel electrophoresis. HSF strongly stimulated some acute phase proteins (rat α₂-macroglobulin and α₁-cysteine protease inhibitor, human fibrinogen and α₁-antichymotrypsin) whereas Il-1 strongly stimulated human α₁-acid glycoprotein.

Human PBM derived HSF showed biochemical similarities to another cytokine, Interferonβ₂ (IFNβ₂), that had previously been cloned from fibroblasts and from T-lymphocytes. HSF and 1FNβ₂ showed immunological similarities on the basis of antibody binding and activity inhibition assays. Cloned IFNβ₂ from T-cells showed potent inducing activity of acute phase protein synthesis and stimulated maximally the same proteins that did HSF. Both human fibroblast cultures and PBM cultures secreted HSF activity and possessed mRNA species that hybridized to a cDNA probe for IFNβ₂. These data suggest that human PBM derived HSF and human IFNβ₂. These data suggest that human PBM derived HSF and human IFNβ₂ are identical and that fibroblasts and T-lymphocytes as well as monocytes are capable of releasing Hepatocyte Stimulating Factor/lnterferonβ₂.

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