IL-7: AhR We Ready for a New Cytokine to Fight Colitis?

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcriptional factor ubiquitously expressed in vertebrate cells. AhR recognizes man-made synthetic compounds such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) and naturally occurring compounds such as the tryptophan derivative indole-3-carbinol (I3C), which is present in cruciferous vegetables; AhR is thought to be involved in the metabolism or detoxification of these compounds [1]. Upon ligand binding, AhR translocates from the cytosol to the nucleus, dimerizes with the aryl hydrocarbon receptor nuclear translocator (AhRNT), and initiates the transcription of target genes with promoters containing the xenobiotic-responsive element (XRE) consensus sequence. The targets of this pathway include genes that encode xenobiotic-metabolizing enzymes, including cytochrome P450 family 1A1 (CYP1A1). The AhR pathway not only functions in the metabolism of man-made and naturally occurring chemicals, but also regulates a variety of physiological processes [2]. In particular, this pathway acts as a crucial regulator of mucosal immunity in the gut [3]. Notably, there is accumulating evidence that activation of AhR is beneficial for colitis in mice and humans [4]. For instance, treatment with TCDD or AhR agonist 6-formylindolo(3, 2-b) carbazole (FICZ) protects mice against dextran sulfate sodium (DSS)-induced colitis [5, 6]. In humans, intestinal T cells and natural killer cells isolated from Crohn’s disease patients express low levels of AhR [6]. Although the precise mechanisms remain to be determined, it is very likely that activation of the AhR in the gut ameliorates colitis by activating intestinal RORct innate lymphoid cells (type 3 ILCs) to release the gut-protective cytokine IL-22 [7] or by augmenting the functions of intestinal intraepithelial lymphocytes (IELs) [8]. Both of these cell types are important for maintaining intestinal homeostasis. In this issue of Digestive Diseases and Sciences, Ji et al. [9] have added a new and indispensable candidate, IL-7, to the list of factors involved in amelioration of colitis by the AhR pathway. Specifically, they reported that FICZ downregulates epithelial cell-derived IL-7 expression inmicewith DSS-induced colitis, concomitant with amelioration of colitis, elevation of intestinal T cell receptor (TCR) c/d IEL subpopulations, and reductions in intestinal-activated CD4CD8 IEL subpopulations. IL-7 plays an essential role in the development and homeostasis of T cells [10]. Recent studies also highlight the importance of IL-7 in intestinal homeostasis; specifically, IL-7 produced by intestinal epithelial cells is essential for the maintenance and functionality of colitogenic memory T cells and intestinal IELs [11, 12]. The identification of IL-7 as a novel target of the AhR pathway in the gut provides new insight into previously unknown aspects of the biology of the AhR pathway in the mucosal immune system. In light of these observations, it will be of interest to determine how environmental and dietary AhR ligands affect epithelial cell-derived IL-7 and influence the development and maintenance of mucosal T cells. In this context, future studies should attempt to reveal how FICZ or activation of the AhR pathway downregulates epithelial cell-derived IL-7 in the gut. Direct activation of the AhR expressed in intestinal type 3 ILCs or IELs is important for amelioration of colitis [7, & Atsuhito Nakao anakao@yamanashi.ac.jp