Molecular mechanism of action of anti-tumor necrosis factor antibodies in inflammatory bowel diseases

Abstract

Anti-tumor necrosis factor (TNF) antibodies are successfully used in the therapy of inflammatory bowel diseases (IBD). However, the molecular mechanism of action of these agents is still a matter of debate. Apart from neutralization of TNF, influence on the intestinal barrier function, induction of apoptosis in mucosal immune cells, formation of regulatory macrophages as well as other immune modulating properties have been discussed as central features. Nevertheless, clinically effective anti-TNF antibodies were shown to differ in their mode-of-action in vivo and in vitro. Furthermore, the anti-TNF agent etanercept is effective in the treatment of rheumatoid arthritis but failed to induce clinical response in Crohn's disease patients, suggesting different contributions of TNF in the pathogenesis of these inflammatory diseases. In the following, we will review different aspects regarding the mechanism of action of anti-TNF agents in general and analyze comparatively different effects of each anti-TNF agent such as TNF neutralization, modulation of the immune system, reverse signaling and induction of apoptosis. We discuss the relevance of the membrane-bound form of TNF compared to the soluble form for the immunopathogenesis of IBD. Furthermore, we review reports that could lead to personalized medicine approaches regarding treatment with anti-TNF antibodies in chronic intestinal inflammation, by predicting response to therapy.

Keywords: Apoptosis; Crohn’s disease; Lamina propria mononuclear cells; Mucosal immunology; Transmembrane tumor necrosis factor; Ulcerative colitis.

Figure 1

Expression of membrane-bound tumor necrosis factor in the gut. Gut tissue of patients with Crohn’s disease (CD) was cryo-frozen and stained for cell markers by immunofluorescence. Nuclei were counterstained with DAPI. A: Staining for mTNF (green). B: Staining for mTNF (green) and CD14 (red). Co-expressing cells are labeled with an arrow.

Figure 2

Mechanism of action of anti-tumor necrosis factor antibodies in inflammatory bowel disease. Schematic illustration of different modes of action of anti-TNF antibodies in inflammatory bowel diseases. TNF: Tumor necrosis factor; mTNF: Membrane-bound TNF; sTNF: Soluble TNF; TNFR: TNF receptor; NK cell: Natural killer cell; ADCC: Antibody-dependent cellular cytotoxicity; CD: Crohn’s disease; CDC: Complement-dependent cytotoxicity; LPS: Lipopolysaccharide.