Disruption of inflammatory signals by cytokine-targeted therapies for inflammatory bowel diseases

Abstract

Gut inflammation occurring in patients with inflammatory bowel diseases (IBD) is associated with an excessive immune response that is directed against constituents of the normal bacterial flora and results in the production of large amounts of inflammatory cytokines. Anti-cytokine compounds, such as the neutralizing TNF antibodies, have been employed with clinical success in patients with IBD. However, nearly half of IBD patients are refractory to such treatments, response can wane with time, and anti-TNF treatment can associate with severe side effects and/or development/exacerbation of extra-intestinal immune-mediated pathologies. These observations, and the demonstration that, in IBD, the pathological process is also characterized by defects in the production and/or activity of counter-regulatory cytokines, have boosted further studies aimed at delineating novel strategies to combat the IBD-associated tissue-damaging immune response.

Figure 1

Schematic view of potential targets and site of action of some biologics in IBD. Following stimulation with bacterial products/components, antigen presenting cells (APCs) produce IL-12, which facilitates the differentiation of Th1 cells. Moreover, APCs make IL-23 and IL-6, which contribute to the polarization and expansion of Th17 cells. Briakinumab and ustekinumab, two monoclonal antibodies directed against p40, a subunit shared by IL-12 and IL-23, could interfere with the activation of both Th1 and Th17 cells. Commitment of naive T cells along the Th17 cell pathway and survival of such cells could also be inhibited by tocilizumab, an antibody blocking IL-6 signalling. The biological activity of IFN-γ, a typical Th1 cytokine, can be suppressed by fontolizumab, while anti-TNF antibodies include infliximab, adalimumab and certolizumab. Th17-derived cytokines, such as IL-17A and IL-21, contribute to amplify the ongoing mucosal inflammation by stimulating epithelial cells to make chemokines, thus enhancing the recruitment of inflammatory cells to the intestinal lamina propria. TNF and IL-21 can also stimulate fibroblasts to synthesize MMPs, a family of enzymes that play a major role in the mucosal degradation and tissue damage occurring in IBD. Moreover, IL-21 enhances the production of IFN-γ by Th1 cells, thereby expanding Th1 cell responses. Attenuation of the mucosal inflammation could be obtained using IL-22, a cytokine made by both Th17 cells and Th22 cells, which targets epithelial cells and stimulates the production of defensins and mucins. In IBD, there is a defective activity of TGF-β1, a powerful anti-inflammatory cytokine, due to high Smad7. Smad7 is an inhibitor Smad that interacts with type I TGF-β receptor and prevents Smad3/3 phosphorylation, a phenomenon that is induced by activated type I TGF-β receptor following binding of TGF-β1 to type II TGF-β receptor. Inhibition of TGF-β-induced Smad2/3 phosphorylation by Smad7 prevents the interaction of Smad2/3 with Smad4 and subsequent migration of the complex to the nucleus, where Smad2/3+Smad4 inhibit the expression of many inflammatory genes. Therefore, inhibition of Smad7 with a specific antisense oligonucleotide could restore TGF-β1 activity and facilitate the resolution of the inflammatory process.