This information is current as Vivo and Suppresses Cutaneous Inflammation In Regulates Th 17 Signature Gene Expression t γ Pharmacologic Inhibition of ROR Jianfei

Content Provider	Semantic Scholar
Author	Skepner, Jill Ramesh, Radha Trocha, Mark Schmidt, Darby Baloglu, Erkan Lobera, M. José Güerre Carlson, Thaddeus J. Hill, Jonathan Orband-Miller, Lisa A. Barnes, Ashley N. Boudjelal, Mohamed Sundrud, Mark S. Ghosh, Shomir Yang, Jianfei
Copyright Year	2014
Abstract	IL-17–producing CD4 + Th17 cells, CD8 + Tc17 cells, and gd T cells play critical roles in the pathogenesis of autoimmune psoriasis. RORgt is required for the differentiation of Th17 cells and expression of IL-17. In this article, we describe a novel, potent, and selective RORgt inverse agonist (TMP778), and its inactive diastereomer (TMP776). This chemistry, for the first time to our knowledge, provides a unique and powerful set of tools to probe RORgt-dependent functions. TMP778, but not TMP776, blocked human Th17 and Tc17 cell differentiation and also acutely modulated IL-17A production and inflammatory Th17-signature gene expression (Il17a, Il17f, Il22, Il26, Ccr6, and Il23) in mature human Th17 effector/memory T cells. In addition, TMP778, but not TMP776, inhibited IL-17A production in both human and mouse gd T cells. IL-23–induced IL-17A production was also blocked by TMP778 treatment. In vivo targeting of RORgt in mice via TMP778 administration reduced imiquimod-induced psoriasis-like cutaneous inflammation. Further, TMP778 selectively regulated Th17-signature gene expression in mononuclear cells isolated from both the blood and affected skin of psoriasis patients. In summary, to our knowledge, we are the first to demonstrate that RORgt inverse agonists: 1) inhibit Tc17 cell differentiation, as well as IL-17 production by gd T cells and CD8 + Tc17 cells; 2) block imiquimod-induced cutaneous inflammation; 3) inhibit Th17 signature gene expression by cells isolated from psoriatic patient samples; and 4) block IL-23–induced IL-17A expression. Thus, RORgt is a tractable drug target for the treatment of cutaneous inflammatory disorders, which may afford additional therapeutic benefit over existing modalities that target only IL-17A. C D4 + Th17 cells play a central role in the pathogenesis of many autoimmune diseases, including psoriasis, rheu-matoid arthritis, inflammatory bowel disease, and multiple sclerosis (1–3). Th17 cells are characterized by their production of IL-17A (i.e., IL-17), IL-17F, and IL-22. In addition to promoting inflammatory tissue injury, these cytokines are important for host defense against mucosal bacteria and fungi (4). Fully human mAbs targeting IL-17 and the IL-17RA have shown clinical efficacy in psoriasis, rheumatoid arthritis, and uveitis (3, 5, 6). Like other ef-fector T cell subsets, Th17 cells develop from naive precursors in an Ag-and cytokine-dependent manner. Th17 differentiation requires the retinoic acid receptor–related orphan nuclear receptor RORgt (7), which is induced in activated naive T cells upon stimulation with STAT3-activating cytokines, such as IL-6/IL-1b (8). In addition to Th17 cells, RORgt expression and IL-17A production have been described in …
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Alternate Webpage(s)	http://www.jimmunol.org/content/jimmunol/early/2014/02/07/jimmunol.1302190.full.pdf
Alternate Webpage(s)	http://www.jimmunol.org/content/jimmunol/192/6/2564.full.pdf
Alternate Webpage(s)	http://www.jimmunol.org/content/jimmunol/192/6/2564.full.pdf?with-ds=yes
Alternate Webpage(s)	http://www.jimmunol.org/content/jimmunol/early/2014/02/07/jimmunol.1302190.full.pdf?with-ds=yes
Language	English
Access Restriction	Open
Content Type	Text
Resource Type	Article