Record Details
Benzimidazoisoquinolines: a new class of rapidly metabolized aryl hydrocarbon receptor (AhR) ligands that induce AhR-dependent Tregs and prevent murine graft-versus-host disease
ScholarsArchive at Oregon State University
| Field | Value |
|---|---|
| Title | Benzimidazoisoquinolines: a new class of rapidly metabolized aryl hydrocarbon receptor (AhR) ligands that induce AhR-dependent Tregs and prevent murine graft-versus-host disease |
| Names |
Punj, Sumit
(creator) Kopparapu, Prasad (creator) Jang, Hyo Sang (creator) Phillips, Jessica L. (creator) Pennington, Jamie (creator) Rohlman, Diana (creator) O'Donnell, Edmond (creator) Iversen, Patrick L. (creator) Kolluri, Siva Kumar (creator) Kerkvliet, Nancy I. (creator) |
| Date Issued | 2014-02-19 (iso8601) |
| Note | Please view the version of record at http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0088726 Copyright: © 2014 Punj et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. PLoS ONE 9(2): e88726. doi:10.1371/journal.pone.0088726 |
| Abstract | The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that plays multiple roles in regulation of immune and inflammatory responses. The ability of certain AhR ligands to induce regulatory T cells (Tregs) has generated interest in developing AhR ligands for therapeutic treatment of immune-mediated diseases. To this end, we designed a screen for novel Treg-inducing compounds based on our understanding of the mechanisms of Treg induction by the well-characterized immunosuppressive AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We screened a ChemBridge small molecule library and identified 10-chloro-7H-benzimidazo[2,1-a]benzo[de]Iso-quinolin-7-one(10-Cl-BBQ) as a potent AhR ligand that was rapidly metabolized and not cytotoxic to proliferating T cells. Like TCDD,10-Cl-BBQ altered donor CD4+ T cell differentiation during the early stages of a graft versus host (GVH) response resulting in expression of high levels of CD25, CTLA-4 and ICOS, as well as several genes associated with Treg function. The Treg phenotype required AhR expression in the donor CD4+ T cells. Foxp3 was not expressed in the AhR-induced Tregs implicating AhR as an independent transcription factor for Treg induction. Structure-activity studies showed that unsubstituted BBQ as well as 4, 11-dichloro-BBQ were capable of inducing AhR-Tregs. Other substitutions reduced activation of AhR. Daily treatment with 10-Cl-BBQ during the GVH response prevented development of GVH disease in an AhR-dependent manner with no overt toxicity. Together, our data provide strong support for development of select BBQs that activate the AhR to induce Tregs for treatment of immune-mediated diseases. |
| Genre | Article |
| Access Condition | http://creativecommons.org/licenses/by/3.0/us/ |
| Topic | Benzimidazoisoquinolines |
| Identifier | Punj S, Kopparapu P, Jang HS, Phillips JL, Pennington J, et al. (2014) Benzimidazoisoquinolines: A New Class of Rapidly Metabolized Aryl Hydrocarbon Receptor (AhR) Ligands that Induce AhR-Dependent Tregs and Prevent Murine Graft-Versus-Host Disease. PLoS ONE 9(2): e88726. doi:10.1371/journal.pone.0088726 |
