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Pharmacological inhibition of ROR gamma t suppresses the Th17 pathway and alleviates antigen-induced arthritis in-vivo

Guendisch, Ulf and Weiss, Jessica and Ecoeur, Florence and Riker, Julia and Kaupmann, Klemens and Kallen, Joerg and Hintermann, Samuel and Orain, David and Dawson King, Janet and Billich, Andreas and Guntermann, Christine (2017) Pharmacological inhibition of ROR gamma t suppresses the Th17 pathway and alleviates antigen-induced arthritis in-vivo. PLoS ONE, 12 (PLoS O). pp. 1-25. ISSN 1932-6203

Abstract

Retinoic acid receptor-related-orphan-receptor-C (ROR gammat) is the key transcription factor that is driving the differentiation of IL-17 producing T-helper 17 (Th17) cells that are implicated in the pathology of various autoimmune and inflammatory diseases. Based on the importance of RORgammat in promoting Th17-driven pathology, there is considerable interest to develop low-molecular-weight compounds with the aim to inhibit the transcriptional activity of this nuclear hormone receptor. In this article, we describe the in-vitro and in-vivo pharmacology of a potent and selective small-molecular-weight RORgammat inverse agonist. The compound binds to the ligand binding domain (LBD) of RORgammat leading to displacement of a co-activator peptide. We show for the first time that a RORgammat inverse agonist down-regulates permissive histone H3 acetylation and methylation at the IL17A and IL23R promoter regions, thereby providing insight into the transcriptional inhibition of RORgammat-dependent genes. Consitent with this, the compound effectively reduced IL-17A production by polarized human gamma delta T-cells and by T-cells and attenuated transcription of RORgammat target genes. The inhibitor showed good in-vivo efficacy in an antigen-induced arthritis model in rats and reduced the frequencies of IL-17A producing cells in ex-vivo recall assays. In summary, we demonstrate that inhibiting RORgammat by a low-molecular-weight inhibitor results in efficient and selective blockade of the pro-inflammatory Th17/IL-17A pathway making it an attractive target for Th17-mediated disorders.

Item Type: Article
Keywords: transcription factors, inflammation, autoimmunity, cell differentiation, cytokines
Date Deposited: 07 Dec 2017 00:45
Last Modified: 07 Dec 2017 00:45
URI: https://oak.novartis.com/id/eprint/32945

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