Human Gene Set: GSE27241_CTRL_VS_DIGOXIN_TREATED_RORGT
      _KO_CD4_TCELL_IN_TH17_POLARIZING
      _CONDITIONS_UP


Standard name GSE27241_CTRL_VS_DIGOXIN_TREATED_RORGT_KO_CD4_TCELL_IN_TH17_POLARIZING_CONDITIONS_UP
Systematic name M8226
Brief description Genes up-regulated in polarizing CD4 [GeneID=920] Th17 cells: wildtype untreated versus RORC [GeneID=6097] knockout treated by digoxin [PubChem=2724385].
Full description or abstract CD4+ T helper lymphocytes that express interleukin-17 (Th17 cells) have critical roles in mouse models of autoimmunity, and there is mounting evidence that they also influence inflammatory processes in humans. Genome-wide association studies in humans have linked genes involved in Th17 cell differentiation and function with susceptibility to Crohn?s disease, rheumatoid arthritis, and psoriasis1-3. Thus, the pathway towards differentiation of Th17 cells and, perhaps, of related innate lymphoid cells with similar effector functions4, 5, is an attractive target for therapeutic applications. Mouse and human Th17 cells are distinguished by expression of the retinoic acid receptor-related orphan nuclear receptor ROR?t, which is required for induction of IL-17 transcription and for the manifestation of Th17-dependent autoimmune disease in mice6. By performing a chemical screen with an insect cell-based reporter system, we identified the cardiac glycoside digoxin as a specific inhibitor of ROR?t transcriptional activity. Digoxin inhibited murine Th17 cell differentiation without affecting differentiation of other T cell lineages and was effective in delaying the onset and reducing the severity of autoimmune disease in mice. At high concentrations, digoxin is toxic for human cells, but non-toxic synthetic derivatives, 20,22-dihydrodigoxin-21,23-diol (Dig(dhd)) and digoxin-21-salicylidene (Dig(sal)), specifically inhibited induction of IL-17 in human CD4+ T cells. Using these small molecule compounds, we demonstrated that ROR?t is imporant for the maintenance of IL-17 expression in mouse and human effector T cells. These data suggest that derivatives of digoxin can be used as chemical probes for development of ROR?t-targeted therapeutic agents that attenuate inflammatory lymphocyte function and autoimmune disease.
Collection C7: Immunologic Signature
      IMMUNESIGDB: ImmuneSigDB
Source publication Pubmed 21441909   Authors: Huh JR,Leung MW,Huang P,Ryan DA,Krout MR,Malapaka RR,Chow J,Manel N,Ciofani M,Kim SV,Cuesta A,Santori FR,Lafaille JJ,Xu HE,Gin DY,Rastinejad F,Littman DR
Exact source GSE27241_2894_200_UP
Related gene sets (show 9 additional gene sets from the source publication)

(show 36 gene sets from the same authors)
External links
Filtered by similarity ?
Source species Mus musculus
Contributed by Jernej Godec (Dana-Farber Cancer Institute)
Source platform or
identifier namespace		 HUMAN_GENE_SYMBOL
Dataset references (show 1 datasets)
Download gene set format: grp | gmt | xml | json | TSV metadata
Compute overlaps ? (show collections to investigate for overlap with this gene set)
Compendia expression profiles ? NG-CHM interactive heatmaps
(Please note that clustering takes a few seconds)
GTEx compendium
Human tissue compendium (Novartis)
Global Cancer Map (Broad Institute)
NCI-60 cell lines (National Cancer Institute)

Legacy heatmaps (PNG)
GTEx compendium
Human tissue compendium (Novartis)
Global Cancer Map (Broad Institute)
NCI-60 cell lines (National Cancer Institute)
Advanced query Further investigate these 197 genes
Gene families ? Categorize these 197 genes by gene family
Show members (show 200 source identifiers mapped to 197 genes)
Version history 7.3: Moved to ImmuneSigDB sub-collection.

See MSigDB license terms here. Please note that certain gene sets have special access terms.