The production of several pro-inflammatory cytokines is increased in inflammatory bowel diseases (IBD). Experimental models of IBD have further defined the importance of specific cytokines for the induction of mucosal inflammation, by using specific neutralising antibodies, or by silencing cytokine genes in mice by using homologous recombination (knockout mice).'2 Several therapeutic strategies are now being developed that either target pro-inflammatory cytokines or use recombinant anti-inflammatory cytokines in Crohn's disease and ulcerative colitis. Tumour necrosis factor-a (TNF-a) is a cytokine which can transmit signals between immune and other cells, and is involved in (apoptotic) cell death, metabolism, inflammation, thrombosis, and fibrinolysis. In recent years, an important role for TNF-a as a pivotal pro-inflammatory mediator in Crohn's disease has emerged, and this has resulted in the development of several therapeutic strategies that target TNF-a. This brief review discusses the current status of treatments targeting TNF-a and provides an outlook for future development.

Regulation of TNF production Human TNF-a is a member of a large family of proteins and receptors that are involved in immune regulation. 34 The secreted form of TNF-a is a 17 kD, non-glycosylated protein, circulating as a 51 kDhomotrimer that is mainly produced by monocytes, macrophages and T cells. Various stimuli, including endotoxin, superantigens, osmotic stress, and radiation, bring about release of TNF-a. 5 The gene encoding TNF-a is located on the short arm of chromosome 6, between the HIA class I and II loci. 6 The production of TNF-a is firmly regulated at the transcriptional, translational, and post-transcriptional levels, suggesting a needfor protection against unregulated TNF-a release. The transcription ofTNF-a by monocytes is down regulated by pretreatment with corticosteroids and various agents that increase the intracellular cyclic AMP concentration. 7 Like other pro-inflammatory cytokines, TNF-a mRNA contains various UAUUAU-rich regions (" Kamen and Shaw regions") within the 3'untranslated region which greatly reducemRNA half-life by acting as an RNAse attack site and by reducing the translation rate. 8 TNF-a is translated as a 26 kD precursor protein that contains an unusually long aminoacid signalpeptide. The enzyme that cleaves the propeptide to yield the secreted mature form has been identified as a specific metallo-proteinase. Unclipped TNF-a remains membrane bound and is biologically active upon contact with neighbouring cells. 9 Various metalloproteinase inhibitors reduce the release of TNF-a, having no significant effect on the number of membrane expressed TNF-a molecules.'"'2 Two specific transmembrane receptors, the type I 55 kD and the type II 75 kD TNF receptors, are expressed by most types of cells studied.'3 The type II 75 kD TNF receptor is also a receptor for lymphotoxin (also known as tumour necrosis factor-,). The events leading to signalling