A monocyte-keratinocyte-derived co-culture assay accurately identifies efficacies of BET inhibitors as therapeutic candidates for psoriasiform dermatitis
| Autor: | Samuel T Hwang, Zhenrui Shi, Daisuke Yamada, Daniel K. Hsu, Lindsay Mendoza, Joshua Chong, Xuesong Wu, Mindy Huynh |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Pyridones Cell Drug Evaluation Preclinical Administration Oral Dermatology Pharmacology Biochemistry Monocytes Proinflammatory cytokine Epigenesis Genetic 030207 dermatology & venereal diseases 03 medical and health sciences Mice 0302 clinical medicine In vivo Psoriasis Cell Line Tumor medicine Animals HaCaT Cells Humans Molecular Biology Skin Sulfonamides Imiquimod Chemistry Monocyte medicine.disease In vitro Coculture Techniques Bromodomain HaCaT Disease Models Animal 030104 developmental biology medicine.anatomical_structure Acetanilides Female Inflammation Mediators Heterocyclic Compounds 3-Ring |
| Zdroj: | Journal of dermatological science. 100(1) |
| ISSN: | 1873-569X |
| Popis: | Background Bromodomain and extra-terminal (BET) proteins perform key roles in epigenetic control of gene expression that is involved in inflammatory conditions, including psoriasiform dermatitis (PsD). Predicting which (of many potential available BET inhibitors) will be effective in vivo is challenging. Objective We determine if a novel in vitro assay that includes two critical cell types involved in human psoriasis can predict the therapeutic potential of specific BET inhibitors in vivo. Methods An in vitro model consisting of U-937 and HaCaT cell co-culture was created to screen small molecule BET antagonists for inhibition of cutaneous inflammatory genes. Efficacious BET inhibitors were tested in a mouse imiquimod (IMQ)-induced PsD model. Results In the co-culture system, HaCaT cells exhibited a marked increase in the secretion of a characteristic set of proinflammatory and Th17-associated cytokines. Of the ten commercially-available small molecules targeting BET proteins assayed, most compounds exhibited inhibitory functions at 1 μM against inflammatory activation, but responded variably at lower concentrations. OTX015, a typical representative for most of the compounds, barely inhibited the inflammatory reactions at 0.1 μM. By contrast, ABBV075 was effective in concentrations as low as 0.01 μM. While oral administration OTX015 in IMQ-treated mice reduced disease severity, ABBV075 equally decreased the symptoms and molecular and cellular severity markers at one-tenth of the minimal dosing required for OTX015. Conclusion In vitro screening system combined with an in vivo animal model, can serve as a convenient pre-clinical screening tool for the selection of BET inhibitors (and possibly other drugs) that may have clinical potential in psoriasis therapy. |
| Databáze: | OpenAIRE |
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