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Review
. 2019 Apr 30;8(5):397.
doi: 10.3390/cells8050397.

Controlling Gut Inflammation by Restoring Anti-Inflammatory Pathways in Inflammatory Bowel Disease

Paolo Giuffrida  1 , Sara Cococcia  2 , Mariangela Delliponti  3 , Marco Vincenzo Lenti  4 , Antonio Di Sabatino  5
Affiliations
Review

Controlling Gut Inflammation by Restoring Anti-Inflammatory Pathways in Inflammatory Bowel Disease

Paolo Giuffrida et al. Cells. .

Abstract

Inflammatory bowel disease (IBD) is caused by a dysregulated immune response against normal components of the intestinal microflora combined with defective functioning of anti-inflammatory pathways. Currently, all therapies approved for IBD manipulate the immune system by inhibiting pro-inflammatory mechanisms, such as tumor necrosis factor-α, gut-homing α4β7 integrin, interleukin-12/interleukin-23, and Janus kinases. However, some IBD patients are non-responders to these drugs, which are also associated with serious side effects. Thus, it has been hypothesized that therapies aimed at restoring anti-inflammatory signals, by exploiting the tolerogenic potential of cytokines (interleukin-10, transforming growth factor-β, granulocyte macrophage colony-stimulating factor), immune cells (regulatory T cells, tolerogenic dendritic cells), or mesenchymal stem cells, might offer promising results in terms of clinical efficacy with fewer side effects. In this review, we provide new insights into putative novel treatments aimed at restoring anti-inflammatory signaling pathways in IBD.

Keywords: Crohn’s disease; granulocyte macrophage colony-stimulating factor; interleukin-10; mesenchymal stem cells; regulatory T cells; tolerogenic dendritic cells; transforming growth factor-β; ulcerative colitis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of the anti-inflammatory mechanisms dampening the inflammation in the gut. Upon stimulation of transforming growth factor (TGF)-β and retinoic acid (RA) from epithelial cells and granulocyte macrophage colony-stimulating factor (GM-CSF) from macrophages, dendritic cells (DCs) become tolerogenic, thus promoting the differentiation of regulatory T cells (Tregs) from naive T cells in healthy gut. Sargramostim and autologous tolerogenic DCs resume the function of GM-CSF and tolerogenic DCs themselves, respectively. In addition to tolerogenic DCs, Tregs inhibit development of T helper 1 (Th1) and Th17 cells by producing TGF-β and interleukin (IL)-10 in healthy gut. Autologous Tregs reinstate Treg function. Mongersen reactivates TGF-β signaling, whereas Tenovil, IL-10 administered through genetically-modified Lactobacillus lactis (LL-Thy12), Alequel, and otelixizumab restore IL-10. Mesenchymal stem cells (MSCs) induce an increase in the number of Tregs.
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