The Role of Tumour Necrosis Factor in Lymphoid Tissue Formation and Function

Abstract

Tumour necrosis factor and lymphotoxin-α (TNF and LTα) are multipotent cytokines showing a wide range of activities that extend beyond their well characterised pleiotropic proinflammatory properties to include diverse signals for cellular differentiation, proliferation and death. TNF is produced in response to various stimuli mainly by macrophages and T cells and is shown to be bioactive both as a transmembrane protein and as a homotrimeric secreted molecule (Vasali, 1992; Kriegler et al, 1988). LTα, originally identified as a major product of lymphocytes, exists as a secreted molecule only in a homotrimeric form (Paul and Ruddle, 1988), but it may also accumulate on the cellular membrane of lymphocytes when complexed with LTβ, a type II transmembrane protein that is another member of the TNF ligand family (Browning et al, 1993). LTα1β2 trimers signal exclusively through the LTα receptor(s) (Crowe et al, 1994), while TNFα and LTα share the same cell surface receptors, designated p55 and p75 TNF-R, which show common but also differential activities depending on the cell type in which they operate (Vandenabeele et al, 1995). p75 TNF-R signalling has been mainly implicated in lymphocyte proliferation (Espevik et al, 1990; Tartaglia et al, 1991) while the p55 TNF-R is generally known to mediate apoptosis (Tartaglia et al, 1993), a process in which the p75 TNF-R mav also be involved (Grell et al. 1995: Zheng et al, 1995).