An aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress the Th17 response in allergic rhinitis patients

Abstract

A predominant Th17 population is a marker of allergic rhinitis (AR). The aryl hydrocarbon receptor (AhR) exhibits strong immunomodulation potential via regulation of the differentiation of T lymphocytes and dendritic cells (DCs) after activation by its ligand, such as 2-(1 0 H-indole-3 0 -carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE). The aim of this study was to analyze the effect of AhR on Th17 differentiation by investigating the action of ITE on DCs and CD4 þ T cells from patients with AR. In all, 26 AR patients and 12 healthy controls were included in this study. The expression of interleukin (IL)-1b, IL-6, IL-10, and IL-17 in the culture supernatant and the presence of Th17 cells in CD4þ T cells and DC-CD4 þ T-cell co-culture system were measured before and after treatment with ITE. We show that ITE significantly induced cell secretion of IL-10 and inhibited IL-1b and IL-6 production in DCs, and promoted IL-10 production and suppressed IL-17 expression in CD4 þ T cells in vitro. It also suppressed the expansion of Th17 cells in vitro. Our work demonstrates that ITE acts on DCs and CD4 þ T cells to inhibit the Th17 response that suppresses AR; the AhR-DC-Th17 axis may be an important pathway in the treatment of AR. ITE, a nontoxic AhR ligand, attenuated the Th17 response; thus, it appears to be a promising therapeutic candidate for suppressing the inflammatory responses associated with AR.

Binding Mode and Structure–Activity Relationships of ITE as an Aryl Hydrocarbon Receptor (AhR) Agonist

“…Resultsh ighlightedf ingerprint residues of the receptor involved in binding and activity of ITE (7), as well as identified the thiazole ring as ak ey pharmacophoric elemento ft he ligand structure. Collectively,r esults of docking studies, MD simulations, and mutagenesis experiments are consistent with SAR obtained from aseries of ITE analogues (9)(10)(11)(12)(13)(14)(15)(16), supporting the experimentalv alidity of the proposed binding mode of ITE (7)t oA hR PAS-B. They pinpoint that p-p stacking interactions, rather than hydrophobic contacts, and specific hydrogen bonds to the central heteroaromatic ring and methyle ster moiety are important forl igand bindinga nd potency to AhR, respectively.T his information will be instrumental to enable new ITE analogue design and/or structure-based approaches for the development of novel AhR modulators in the search for novel immune-regulatory and anticancer therapeutic agents.…”

“…Figure 10. Structure of ITE analogues (9)(10)(11)(12)(13)(14)(15)(16), which were tested in biological assays. ChemMedChem 2018, 13,270 -279 www.chemmedchem.org bered aromatic groups with different HOMO and LUMO energies (Table1).…”

“…Figure 11. Transactivation activity of AhR by ITE (7)and different ITE derivatives (9)(10)(11)(12)(13)(14)(15)(16). Hepatic H1L1 cells were transfected with wild-type or different AhR mutants: AhR(H285A), AhR(Q377A), AhR(Y316A),orAhR(Y316A/Q377A).…”

“…[10] Likewise, AhR activation hasb een shown to inhibitt he Th17 inflammatory response, regulating both DCs and CD4(+) Tcells derived from patients with allergic rhinitis. [11] Besides affecting differentiation and functions of Th17/Treg cells, additional AhR-mediated immunological effects of ITE (7)h ave emerged, specifically,t he ability of the compound to suppress Bcell differentiation into Ig-secreting plasma cells. [12] AhRmediated anticancer activities of ITE (7)h ave also been reported, including the suppression of proliferation and migration of ovarian cancerc ells [13] and reduction of the tumorigenicp otential of stem-like cancerc ells in orthotopic xenograft tumor models.…”

Tryptophan: ‘essential’ for the pathogenesis of irritable bowel syndrome?

“…It was also shown recently that kynurenine activates mast cells via AhR [ 38 ] and that AhR is upregulated in allergic rhinitis [ 39 ] and can be inhibited by another (non-toxic) tryptophan metabolite (abbreviated to ITE) [ 40 ]. These metabolites present very interesting possibilities for developing new treatments for allergies.…”