Genetic Regulation of the Hepatic Acute Phase Response

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DESCRIPTION (provided by applicant): Tissue damage initiates a local inflammatory reaction that is designed to mobilize the acute phase response, which provides an immediate defense mechanism for the organism. Induced production of acute phase proteins (APPs), e.g., haptoglobin (HP) and a1-acid glycoprotein (AGP), along with sustained high-level expression of a1 -proteinase inhibitors (a1 -PT) are key systemic reactions to inflammation. The APPs function in the removal of harmful products of inflammation. Modification of expression of these APPs in mice suggest that they also contribute to the resolution of inflammation, in part, by reducing tissue-damaging reactions elicited by inflammatory leukocytes (particularly neutrophils and monocytes/macrophages). It is hypothesized that HP, AGP and a1-PI act as anti-inflammatory agents through modulation of the activities of inflammatory leukocytes. Since tumor growth is invariably associated with infiltration of such cells, it is also hypothesized that inflammation supports tumor cell proliferation, and this effect is regulated by APPs. In the current proposal, these hypotheses will be tested through the use of transgenic and gene knockout mouse models. The following aims are proposed: (1) to determine whether HP and AGP control the activity of neutrophils and promote anti-inflammatory reactions in monocytes/macrophages, and whether the cell surface receptors for these APPs functionally contribute to the regulation; (2) to assess the consequence of the APP activities on the course of acute phase reaction and on the proliferation of tumors in vivo; (3) to identify the effects of inflammation-associated proteinases on the cleavage of a1-PI; and (4) to define the role of a1-PI cleavage and inactivation on tumorigenisis. The study will define novel mechanisms by which the inflammatory process is modulated by APPs, and will deepen our understanding of how APPs contribute to chronic disease, such as cancer.