Human lymphotoxins (LT) are a multicomponent family of related and distinct cell lytic and growth inhibitory glycoproteins. There is now evidence that they may have a role as effectors in certain classes of cell-lytic reactions mediated by human lymphocytes in vitro and different classes of lymphocytes can release different LT forms. In these reactions the different LT forms may function to induce cell lysis as either multimeric molecular complexsis or as individual components acting together in a synergistic fashion. Recent data indicates that certain individual LT molecules have other functions as well for they may possess anti-tumor activity and be capable of acting in synergy with human interferons in vitro. What is needed now is the isolation and study of purified key LT forms and determination of how they induce cell-lysis individually and in combination with each other. The alpha component is an important LT form for it can assemble into molecular complexsis, may have antitumor effects, can synergize with human IFN, and may serve as a precursor for several smaller LT forms. One of the major problems of studies with human LT is that they are only available in small quantities, difficult to purify, and have not been available in pure form for biochemical and functional studies. We have developed methods to stimulate, produce, and purify significant quantities of alpha LT from IR 3.4 cells (a continuous human lymphoblastoid cell line). Using purified alpha LT and in vitro systems we will examine: A) the effectiveness of this cell toxin on various types of target cells, B) if this toxin has selective anti-tumor effects, C) the molecular mechanism(s) of LT induced cell lysis, D) the molecular basis of cell sensitivity and resistance, and E) the mechanism(s) operative in synergistic action of purified LT and human IFN on cells.
| Knauer, M F; Longmuir, K J; Yamamoto, R S et al. (1990) Mechanism of human lymphotoxin and tumor necrosis factor induced destruction of cells in vitro: phospholipase activation and deacylation of specific-membrane phospholipids. J Cell Physiol 142:469-79 |
