Description
Tumor Necrosis Factor (TNF) was originally discovered as a serum protein with necrotizing effects on certain transplantable mouse tumors in vivo and cytotoxic effects against some transformed cells in vitro. The TNF family consists of two proteins designated TNF-alpha, also called cachectin, and TNF-beta, also called lymphotoxin, which are pleiotropic cytokines that can mediate a wide variety of biological effects. TNF-beta is produced by activated lymphocytes, whereas TNF-alpha is mostly produced by activated macrophages. Soluble TNF-beta is a T-cell derived glycoprotein of 25 kD. TNF-beta is induced in an antigen-specific MHC restricted fashion from class I and class II restricted T cells. Viral infection is also associated with TNF-beta production by lymphoid cells. TNF-beta has several effects on target cells including killing, growth stimulation, induction of adhesion molecule (ICAM-1) expression, and induction of differentiation. The mechanisms of TNF-beta effects involve receptor binding and internalization and several sequelae including changes in prostaglandins and chromosome integrity. TNF-beta participates in tumor immunity, and it has been reported to inhibit carcinogenesis as well as growth of some tumors in vivo. Recent studies have demonstrated that both TNF-alpha and TNF-beta are capable of activating neutrophils in vitro. The exposure of neutrophils to TNF-alpha or TNF-beta causes the production of superoxide radicals, induces phagocytic response and enhances antibody dependent cell cytotoxicity. The release of IL-1 from human endothelial cells is also induced by TNF-alpha and TNF-beta. All the in vitro studies suggest that TNF-beta may play an important role in immunoregulation. In fibroblasts TNF-beta induces the synthesis of colony-stimulating factors, IL-1, collagenase and prostaglandin-E2. Monocytes are stimulated for terminal differentiation. On B-cells TNF-beta acts as mitogen. As TNF-beta exerts proliferative capacity on fibroblasts it may participate in the process of wound healing. While both TNFs inhibit growth of tumor cells, they stimulate the growth of human lung fibroblasts and dermal fibroblasts. TNF-beta also acts as antiviral agent against a variety of RNA (VSV and EMCV) and DNA (Ad-2 and HSV-2) viruses and its activity is potentiated by interferongamma in a synergistic fashion. Moreover, TNF-beta contributes to the defense against parasitic infections and induces osteoclastic bone resorption and inhibition of bone collagen synthesis. The elucidation of the physiological and pathophysiological role was limited due to a lack of adequate assay systems. The present assay developed by Adolf and Lamche provides a simple and rapid method for determination of serum levels of TNF-beta with a minimal detectable dose as low as 7 pg/ml serum. This assay will help to clarify the possible diagnostic and prognostic value of circulating TNF-beta in various neoplastic and inflammatory diseases. The assay detects recombinant, unglycosylated lymphotoxin with the same sensitivity as the natural, glycosylated protein, shows good correlation with the standard cytotoxicity bioassay, and is specific for biologically active TNF-beta without TNF-alpha cross reactivity