Abstract
RORγT is a protein product of the RORC gene belonging to the nuclear receptor subfamily of retinoic-acid-receptor-related orphan receptors (RORs). RORγT is preferentially expressed in Th17 lymphocytes and drives their differentiation from naive CD4+ cells and is involved in the regulation of the expression of numerous Th17-specific cytokines, such as IL-17. Because Th17 cells are implicated in the pathology of autoimmune diseases (e.g., psoriasis, inflammatory bowel disease, multiple sclerosis), RORγT, whose activity is regulated by ligands, has been recognized as a drug target in potential therapies against these diseases. The identification of such ligands is time-consuming and usually requires the screening of chemical libraries. Herein, using a Tanimoto similarity search, we found corosolic acid and other pentacyclic tritepenes in the library we previously screened as compounds highly similar to the RORγT inverse agonist ursolic acid. Furthermore, using gene reporter assays and Th17 lymphocytes, we distinguished compounds that exert stronger biological effects (ursolic, corosolic, and oleanolic acid) from those that are ineffective (asiatic and maslinic acids), providing evidence that such combinatorial methodology (in silico and experimental) might help wet screenings to achieve more accurate results, eliminating false negatives.
Highlights
Th17 lymphocytes are one of the subsets of T-helper cells that secrete proinflammatory cytokines, including IL-17A, IL17F, IL-21, IL-22, and GM-CSF2
The overactivation of Th17 cells is associated with the pathogenesis of certain autoimmunological diseases, such as psoriasis [6], psoriatic arthritis [7], rheumatoid arthritis [8], multiple sclerosis [9], Crohn’s disease [10], and ankylosing spondylitis [11]
RORγT is considered a master regulator of Th17 differentiation [12]. This transcription factor belongs to the nuclear receptor subfamily of retinoic-acid-receptor-related orphan receptors (RORs), which includes RORα (NR1F1) and RORβ (NR1F2) [13,14], and is one of two isoforms of the RORC gene (NR1F3)
Summary
Th17 lymphocytes are one of the subsets of T-helper cells that secrete proinflammatory cytokines, including IL-17A, IL17F, IL-21, IL-22, and GM-CSF2. These lymphocytes contribute to pathogen (e.g., Bacillus anthracis [1], Candida albicans [2], Staphylococcus aureus [3]). RORγT is considered a master regulator of Th17 differentiation [12]. This transcription factor belongs to the nuclear receptor subfamily of retinoic-acid-receptor-related orphan receptors (RORs), which includes RORα (NR1F1) and RORβ (NR1F2) [13,14], and is one of two isoforms of the RORC gene (NR1F3). Among the compounds that interact with the RORγT ligand-binding protein are agonists that activate the receptor [22] and inverse agonists that inhibit the activity of the receptor [23]
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