Transgenic Models of Chronic Arthritis and of Systemic Tumour Necrosis Factor-Mediated Disease in Mice Expressing Human Tumour Necrosis Factor

Abstract

Tumour necrosis factor (TNF-α/cachectin, TNF) was discovered originally as a factor displaying cytotoxic/cytostatic effects on transformed cells in vitro and necrotizing activity on certain transplantable tumours in vivo (Carswell et al. 1975). In later studies, TNF was shown to be the primary mediator of wasting accompanying chronic invasive diseases (Beutler et al. 1985; Tracey et al. 1986). Acting in concert with other members of the cytokine network, TNF has now been clearly established as a central regulator of inflammation and immunity, mainly

Table 1. In vivo activities of TNF — context, rate and duration of TNF — synthesis

Homeostasis

Differentiation — tissue remodelling

Induction of cytokine cascades — synergy

Inflammation

Cellular immunity — infectious diseases

Cytotoxicity — tissue destruction

Vascular thrombosis and tumour necrosis

Cachexia and wasting toxicity

Shock and death

by modulating the functional state of cells that participate in such processes (reviewed by Beutler and Cerami 1989; Old 1990). For example, it has been shown that TNF augments the cytotoxicity of macrophages (Esparza et al. 1987), induces neutrophil adhesion and activation (Gamble et al. 1985) and regulates T and B cell growth and differentiation (Shalaby et al. 1988). The cell-specific effects of TNF are also exerted in a number of nonimmune cell types. The hemostatic properties of vascular endothelial cells are found to be modulated by TNF which induces the production of procoagulant activity (Nawroth and Stern 1986) and enhances the expression of adhesion molecules that bind neutrophils and monocytes (Gamble et al. 1985). Moreover, TNF is shown to be a growth factor for normal fibroblasts (Vilcek et al. 1986) and thymocytes (Ranges et al. 1988) and to interfere with the metabolism of adipocytes (Semb et al. 1987). In response to TNF many cell types are found to increase the production of several other factors, including IL-6, IL-1, colony stimulating factors, collagenase, PGE₂, c fos, c-myc and histocompatibility antigens. Fine tuning of such circuits is very important to the defence of the host and to the restoration of homeostasis in the body following a microbial infection or a tissue injury.