Transforming growth factor and intestinal inflammation: the role of nutrition.

ABSTRACT

The intestinal mucosa possesses a complex epithelial barrier and a well-organized local immune system, which both efficiently protect this internal-external surface against potential microbial aggressions while guaranteeing tolerance towards harmless bacteria or antigens (oral tolerance). There is good experimental evidence that the intestinal microbiota is a main driver for the development of the mucosal immune system. Any perturbations/changes of this interaction with the intestinal microbiota or the microbial colonization process may cause health problems with short- and eventually long-term consequences, such as suspected for allergic or dysimmune disorders. Dendritic cells (DC) play a key role in the initiation of immune responses. Immune responses elicited by intestinal DC differ markedly from those initiated by spleen-derived DC while intestinal DC induce anti-inflammatory and tolerogenic responses to harmless antigens such as derived from the resident microflora or harmless food allergens, systemic immune activation yields in a strong inflammatory TH1/TH17 reaction to the same antigens. The recent discovery how DC functions are regulated and imprinted by the microenvironment (DC conditioning) will be discussed in this review. High concentrations of retinoic acid or vitamin D metabolites, thymic stromal lymphopoietin and/or transforming growth factor-ß (TGF-ß) activate signaling programs in DC that yield in priming of regulatory and anti-inflammatory T cell responses. TGF-ß is one of the key factors implicated in intestinal immune regulation; it is produced by a large variety of cells in the intestinal mucosa, including intestinal epithelial cells, lymphocytes and monocytes/macrophages/DC. An important anti-inflammatory effect of TGF-ß on the immune system is the promotion and generation of FOXP3-positive regulatory T cells in the intestinal compartment. There are first and encouraging data from the treatment of Crohn's disease, an inflammatory GI condition, that targeted enteral therapy with optimized concentrations of immunoregulatory peptides, such as TGF-ß, might of interest for the treatment of inflammatory disorders.