Regulation of tumor necrosis factor and interferon-gamma release from lymphokine-activated killer cells.
AdvisorYocum, David E.
MetadataShow full item record
PublisherThe University of Arizona.
RightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
AbstractPeripheral blood lymphocytes cultured in interleukin 2 (IL-2) acquire the ability to lyse tumor cell targets in a non-major histocompatability complex (MHC) restricted manner. These lymphokine activated killer (LAK) cells release tumor necrosis factor-alpha (TNF) and interferon-gamma (IFN-γ) in culture and when stimulated by interaction with tumor cells in vitro. The capacity of several suppressive factors to affect the release of TNF and IFN-γ from LAK cells which have been stimulated with K562 erythroleukemia cells was investigated. A number of agents known to inhibit mononuclear phagocyte secretion of TNF were tested, including prostaglandin E₂ (PGE₂), alpha-globulins and the synthetic protease inhibitor tosyl-arginine methyl ester (TAME). The alpha globulins and TAME are thought to suppress TNF release from monocytes by inhibiting proteolytic cleavage of the cytokine from the cell surface. The addition of PGE₂, whole plasma alpha globulins, purified alpha-1-acid glycoprotein, and TAME inhibited TNF and IFN-γ release in a concentration dependent manner. These inhibitory factors appear to act directly on the lymphocytes to suppress cytokine secretion, as the presence of monocytes or metabolically active tumor cells was not required. The effects of alpha-1-acid glycoprotein on LAK cells were also investigated. The addition of this alpha globulin fraction inhibits the incorporation of ³[H] thymidine by LAK cells stimulated with tumor cells, and results in a detectable decrease in TNF mRNA. The capacity of alpha-1-acid glycoprotein to suppress the release of TNF production also resulted in an inhibition of LAK cell generation which was reversed by the addition of exogenous TNF. In contrast to their suppressive effect on peripheral blood monocytes, the protease inhibitors alpha-1-antitrypsin and alpha-2-macroglobulin enhanced TNF secretion from LAK cells exposed to leukemia cells. Analysis of cell surface TNF expression by fluorescence activated cell sorting (FACS) suggest that the observed differences in regulation reflect the capacity of particular phenotypes to express TNF as a transmembrane molecule. The data presented here indicate that the regulation of TNF release by LAK cells stimulated with tumor cells differs significantly from that previously observed in monocytes and suggest a regulatory role for alpha-1-acid glycoprotein in TNF secretion by LAK cells.
Degree ProgramMicrobiology and Immunology