title: In vivo regulation of gene expression and T helper type 17 differentiation by RORγt inverse agonists.
abstract: The orphan nuclear receptor, retinoic acid receptor-related orphan nuclear receptor γt (RORγt), is required for the development and pathogenic function of interleukin-17A-secreting CD4(+) T helper type 17 (Th17) cells. Whereas small molecule RORγt antagonists impair Th17 cell development and attenuate autoimmune inflammation in vivo, the broader effects of these inhibitors on RORγt-dependent gene expression in vivo has yet to be characterized. We show that the RORγt inverse agonist TMP778 acts potently and selectively to block mouse Th17 cell differentiation in vitro and to impair Th17 cell development in vivo upon immunization with the myelin antigen MOG35-55 plus complete Freund's adjuvant. Importantly, we show that TMP778 acts in vivo to repress the expression of more than 150 genes, most of which fall outside the canonical Th17 transcriptional signature and are linked to a variety of inflammatory pathologies in humans. Interestingly, more than 30 genes are related with SMAD3, a transcription factor involved in the Th17 cell differentiation. These results reveal novel disease-associated genes regulated by RORγt during inflammation in vivo, and provide an early read on potential disease indications and safety concerns associated with pharmacological targeting of RORγt.
authors.affiliation: Tempero Pharmaceuticals, GlaxoSmithKline, Cambridge, MA, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Skepner
authors.affiliation: Tempero Pharmaceuticals, GlaxoSmithKline, Cambridge, MA, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Trocha
authors.affiliation: Tempero Pharmaceuticals, GlaxoSmithKline, Cambridge, MA, USA.
authors.forename: Radha
authors.initials: R
authors.lastname: Ramesh
authors.affiliation: Computational Biology, Quantitative Sciences, GlaxoSmithKline, RTP, NC, USA.
authors.forename: Xiaoyan A
authors.initials: XA
authors.lastname: Qu
authors.affiliation: Tempero Pharmaceuticals, GlaxoSmithKline, Cambridge, MA, USA.
authors.forename: Darby
authors.initials: D
authors.lastname: Schmidt
authors.affiliation: Tempero Pharmaceuticals, GlaxoSmithKline, Cambridge, MA, USA.
authors.forename: Erkan
authors.initials: E
authors.lastname: Baloglu
authors.affiliation: Tempero Pharmaceuticals, GlaxoSmithKline, Cambridge, MA, USA.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Lobera
authors.affiliation: Tempero Pharmaceuticals, GlaxoSmithKline, Cambridge, MA, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Davis
authors.affiliation: Tempero Pharmaceuticals, GlaxoSmithKline, Cambridge, MA, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nolan
authors.affiliation: Tempero Pharmaceuticals, GlaxoSmithKline, Cambridge, MA, USA.
authors.forename: Thaddeus J
authors.initials: TJ
authors.lastname: Carlson
authors.affiliation: Tempero Pharmaceuticals, GlaxoSmithKline, Cambridge, MA, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Hill
authors.affiliation: Tempero Pharmaceuticals, GlaxoSmithKline, Cambridge, MA, USA.
authors.forename: Shomir
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Tempero Pharmaceuticals, GlaxoSmithKline, Cambridge, MA, USA.|Department of Cancer Biology, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Sundrud
authors.affiliation: Tempero Pharmaceuticals, GlaxoSmithKline, Cambridge, MA, USA.
authors.forename: Jianfei
authors.initials: J
authors.lastname: Yang
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D005260:Female; D005620:Freund's Adjuvant / Q000276:immunology; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology*; D020869:Gene Expression Profiling; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D007114:Immunization / Q000379:methods; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000819:agonists / Q000235:genetics / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D010446:Peptide Fragments / Q000276:immunology; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
chemical_list: D006576:Heterocyclic Compounds, 4 or More Rings; D063308:Myelin-Oligodendrocyte Glycoprotein; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D010446:Peptide Fragments; C588348:TMP778; C445081:myelin oligodendrocyte glycoprotein (35-55); D005620:Freund's Adjuvant
keywords: T cells; autoinflammatory disease; cytokines