Lymphocyte emigration from the blood into either lymphoid organs or chronic inflammatory sites occurs primarily through unique postcapillary venules (PCV) referred to as high endothelial venules (HEV) because of their content of prominent cuboidal endothelial cells (EC). Previous studies in this laboratory have demonstrated: 1) that interleukin-1 (IL-1), interferon-gamma (lFN-gamma), and tumor necrosis factor-alpha (TNF) all act specifically on cultured EC to enhance their ability to bind B and T cells, the first step in lymphocyte emigration, 2) that lFN- gamma also acts on EC to enhance lymphocyte movement through EC monolayers, the second step in the emigration of lymphocytes, and 3) that lL-1 is a chemotactic factor for lymphocytes and may therefore attract EC-bound lymphocytes toward sites of inflammation in the connective tissue. It is proposed to further investigate the roles of these cytokines in the development of chronic inflammation: 1) by determining whether these cytokines can induce other tall endothelial-like properties in cultured EC such as increased cell volume, increased protein synthesis and increased incorporation of sulfate into macromolecules, as well as induction of specific enzymes commonly observed in EC of HEV in vivo, 2) by investigating the effects of the cytokines on EC proliferation, since neovascularization is necessary for the spread of chronic inflammatory lesions, 3) by characterizing T cell subpopulations with varying degrees of adhesiveness for EC with regard to their chemotactic responsiveness, their cell-surface expression of LFA-1 and very late activation antigens (VLA), and their cell-surface expression of antigenic markers of natural killer cells, helper/inducer cells, suppressor/inducer cells and memory cells, and 4) by determining whether injection of cytokines into experimentally-induced air pouches can induce chronic inflammatory changes in the lining membrane of the pouch, including hyperplasia of the cells of the lining layer, characteristic patterns of mononuclear cell infiltration, EC proliferation and presence of HEV. In the latter study, an effort will be made to relate the specific cytokine injected to the specific pathological changes observed. The results of these experiments should provide useful information about fundamental mechanisms of chronic inflammation.
