TGF-β in inflammatory bowel disease: a key regulator of immune cells, epithelium, and the intestinal microbiota

Abstract

Inflammatory bowel disease (IBD) is defined as chronic intestinal inflammation, and includes ulcerative colitis and Crohn's disease. Multiple factors are involved in the pathogenesis of IBD, and the condition is characterized by aberrant mucosal immune reactions to intestinal microbes in genetically susceptible hosts. Transforming growth factor-b (TGF-b) is an immune-suppressive cytokine produced by many cell types and activated by integrins. Active TGF-b binds to its receptor and regulates mucosal immune reactions through the TGF-b signaling pathway. Dysregulated TGF-b signaling is observed in the intestines of IBD patients. TGF-b signal impairment in specific cell types, such as T-cells and dendritic cells, results in spontaneous colitis in mouse models. In addition, specific intestinal microbes contribute to immune homeostasis by modulating TGF-b production. In this review, we describe the role of TGF-b in intestinal immunity, focusing on immune cells, epithelium, and intestinal microbes. In addition, we present potential therapeutic strategies for IBD that target TGF-b.

Ameliorative effects of riboflavin on acetic acid‐induced colonic injury in rats

“…Several genes encoding fibrillar collagens such as COL1A1 and COL3A1 are upregulated by TGF‐β acting directly through the Smad3 signalling pathway . However, impaired or loss of TGF‐β1 signalling is reported to be associated with the development of colonic inflammation in experimental models and IBD patients . We observed markedly reduced colonic TGF‐β1 protein expression levels compared to control, probably due to the impaired TGF‐β1 expression in the AA‐induced colitis model used in this study.…”

“…38 However, impaired or loss of TGF-β1 signalling is reported to be associated with the development of colonic inflammation in experimental models and IBD patients. 39,40 We observed markedly reduced colonic TGF-β1 protein expression levels compared to control, probably due to the impaired TGF-β1 expression in the AA-induced colitis model used in this study. A possible factor for impaired TGF-β1 expression is Smad7, which is an inhibitor of TGFβ 1 signalling pathway.…”

Intestinal epithelial cells: at the interface of the microbiota and mucosal immunity

“…Among the immunomodulatory molecules that are produced by IECs, thymic stromal lymphopoietin, transforming growth factor (TGF)‐ β , retinoic acid and IL‐10 have been shown to impact a broad range of immune cells and have each earned their own detailed reviews . In addition to these well‐described modulators of immune cell function, IEC production of IL‐15 has recently been shown to be required for the homing of protective T‐cell receptor‐ γδ ‐positive (TCR‐ γδ + ) intraepiethlial lymphocytes (IELs) to the epithelium of the small intestine .…”

“…Among the immunomodulatory molecules that are produced by IECs, thymic stromal lymphopoietin, transforming growth factor (TGF)-b, retinoic acid and IL-10 have been shown to impact a broad range of immune cells and have each earned their own detailed reviews. [65][66][67][68] In addition to these well-described modulators of immune cell function, IEC production of IL-15 has recently been shown to be required for the homing of protective T-cell receptorcd-positive (TCR-cd + ) intraepiethlial lymphocytes (IELs) to the epithelium of the small intestine. 69 The TCR-cd + IEL surveillance behaviour, antimicrobial responses and protection against pathogens such as Salmonella Typhimurium and Toxoplasma gondii are dependent on MyD88 signalling in IECs; 70,71 however, the mechanisms of IEC-IEL communication required for these functions are still unknown.…”

Ulcerative Colitis–Associated Carcinoma: Epithelial SMAD4-Mediated Signaling Is a Key Guardian

“…This SMAD trimer complex (phosphorylated R-Smads-SMAD4)s then translocates to the nucleus where it activates transcription of specific target genes. Over the years, impairments of the TGFβ superfamily signaling pathway in inflammatory bowel disease (IBD) pathogenesis and wound healing process have been studied in experimental models as well as in patients 3, 4, 5. However, the relationship between CAC and specific elements of the TGFβ superfamily signaling, such as the SMADs effectors, has not been studied extensively, with one study investigating the specific role of SMAD7 in lamina propria mononuclear cells as a protective role for CAC in murine models 6 .…”