Binding of Membrane-Bound TNF

Abstract

The efficacy of anti-TNF antibodies in inflammatory bowel diseases (IBD) has been attributed to multiple effects, but the precise molecular mechanism of action has still not been thoroughly characterized. It has been shown that the available anti-TNF agents are able to block soluble TNF in vitro. However, mere neutralization of soluble TNF cannot be the only therapeutic modality of therapeutically efficient anti-TNF agents, as accumulating evidence indicates that effector cells expressing membrane-bound TNF are critically involved in the induction and perpetuation of chronic mucosal inflammation. Transmembrane TNF (mTNF) is characterized by a unique bipolar function in the inflammatory reaction, as it not only can act as a ligand but also mediates reverse signaling into mTNF-expressing cells. Accordingly, it was demonstrated that anti-TNF antibodies exert their main therapeutic properties by binding to mTNF. The anti-TNF antibodies that are therapeutically effective in IBD are able to form more stable immune complexes, with greater avidity in binding to mTNF, than the anti-TNF agent etanercept, which failed to show a therapeutic effect in Crohn's disease patients. Apart from complement-dependent and antibody-dependent cell-mediated cytotoxicity, the induction of apoptosis is regarded as the major therapeutic effect of anti-TNF antibodies in regard to their binding to mTNF-expressing mucosal cells. The distinct mechanisms leading to the induction of programmed cell death include outside-to-inside signaling, resulting in direct induction of apoptosis in mTNF-bearing intestinal cells, and also inhibition of the interaction between mTNF-expressing macrophages and TNFR2-expressing T cells, leading to indirect induction of mucosal T-cell apoptosis. Altogether, current data suggest that mTNF regulation in antigen-presenting cells, rather than in T cells, seems to be the main therapeutic effect of anti-TNF agents in IBD. The decisive role of mTNF in the molecular mechanism of action of anti-TNF antibodies is underscored by the predictive capacity of in vivo mucosal mTNF expression concerning the therapeutic response to subsequent anti-TNF treatment in Crohn's disease patients. Growing understanding of both the pathogenic role of mTNF-expressing mucosal cells in IBD and the interaction of mTNF with anti-TNF antibodies will further contribute to the prediction of therapeutic efficacy, the characterization of molecular targets for forthcoming novel therapies and the development of new anti-TNF agents.