T helper cells that produce Interleukin-17 (IL-17) (TH17 cells) are a recently identified CD4+ T-cell subset with characterized pathological roles in autoimmune diseases. The nuclear receptors retinoic-acid-receptor-related orphan receptors α and γt (RORα and RORγt, respectively) are required for the full differentiation of naïve CD4+ T cells into TH17 cells. SR-1001 is an inverse agonist ligand of RORα/RORγ which dose dependently displaces [3H]25-hydroxycholesterol binding to RORα and RORγ (Ki = 172 and 111 nM, respectively). In HEK293 cells, SR-1001 repressed both GAL4-RORα and GAL4-RORγ transcriptional activity in a dose dependent manner. Also in HEK293 cells transfected with the Il17 reporter and either full-length RORα or RORγ, SR-1001 dose-dependently suppressed the Il17 promoter driven activity by each of the receptors. In EL4 cells expressing RORα, RORγt and IL-17A (Il17α), treatment of cells with SR-1001 suppressed Il17α mRNA expression indicating that SR-1001 suppression of Il17α mRNA expression is RORα/RORγ dependent. In an animal model of TS17 cell-mediated autoimmune disease, 25 mg/kg of SR-1001 b.i.d. i.p. delayed the onset and clinical severity of EAE (experimental autoimmune encephalomyelitis)[3].
作用机制
SR-1001 binds specifically to the ligand binding domains (LBDs) of RORα and RORγt inducing a conformational change within the LBD[3].
SR1001 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Primary mouse keratinocytes (MKCs)
10 µM
20 hours
Evaluate the effect of SR1001 on MC903-induced Tslp expression, SR1001 showed moderate suppression of Tslp expression in vitro
J Invest Dermatol. 2017 Dec;137(12):2523-2531
Human peripheral blood mononuclear cells (hPBMCs)
5 µM
24 hours
To evaluate the effect of SR1001 on IL-17 expression in human PBMCs, results showed that SR1001 inhibited IL-17 expression.
Nature. 2011 Apr 28;472(7344):491-4
EL4 cells
10 µM
24 hours
To evaluate the effect of SR1001 on IL-17A mRNA expression, results showed that SR1001 suppressed Il17a mRNA expression, and this suppression was dependent on ROR α/ROR γ.
Nature. 2011 Apr 28;472(7344):491-4
HepG2 cells
10 µM
24 hours
Suppression of ENHO gene expression
Mol Metab. 2018 Feb;8:51-64
Pancreatic acinar AR42J cells
15 μg/ml
24 hours
To investigate the effect of SR1001 on pancreatic acinar cell apoptosis, results showed that SR1001 significantly reduced cell apoptosis.
Heliyon. 2023 Sep 18;9(9):e20118
CD4+ T cells
15 μg/ml
24 hours
To investigate the effect of SR1001 on Th17 cell differentiation, results showed that SR1001 significantly downregulated Th17 cell differentiation.
Heliyon. 2023 Sep 18;9(9):e20118
Primary mouse keratinocytes (MKCs)
10 µM
4 hours
Evaluate the effect of SR1001 on TPA-induced inflammatory cytokine expression, SR1001 did not significantly block TPA-induced cytokine expression
J Invest Dermatol. 2017 Dec;137(12):2523-2531
Splenocytes
5 µM
5 days
To evaluate the effect of SR1001 on T H17 cell differentiation, results showed that SR1001 inhibited the mRNA expression of Il17a, Il17f, Il21, and Il22.
Nature. 2011 Apr 28;472(7344):491-4
Human monocyte-derived macrophages
10 µM
7 days
SR1001 treatment reduced the expression of the BMAL1 repressor REV ERBα in M1 macrophages and showed a tendency towards reduced viability of the cells. In M2 macrophages, RORβ levels significantly increased.
Front Immunol. 2024 May 28;15:1408772
SR1001 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/6J mice
MC903-induced atopic dermatitis-like disease model and TPA-induced acute irritant dermatitis model
Topical application
0.6 mg (50 mM)
Once daily for 11 days (AD model) or single dose followed by 26-hour observation (acute dermatitis model)
Evaluate the anti-inflammatory effects of SR1001, SR1001 significantly reduced skin inflammation induced by MC903 and TPA, decreasing inflammatory cell infiltration and cytokine expression
J Invest Dermatol. 2017 Dec;137(12):2523-2531
Male C57BL/6J mice
High cholesterol diet model
Intraperitoneal injection
100 mg/kg
Twice daily for 21 days
High cholesterol diet suppressed hepatic Enho expression, SR1001 further suppressed expression
Mol Metab. 2018 Feb;8:51-64
Mice
Depression-like behavior models
Intraperitoneal injection
125 µg
Once daily, starting one day before Th17 cell transfer and continued throughout the experiment
Inhibition of RORγT to reduce Th17 cell differentiation, thereby decreasing depression-like behavior
Biol Psychiatry. 2013 Apr 1;73(7):622-30
Mice
Experimental autoimmune encephalomyelitis (EAE) model
Intraperitoneal injection (i.p.)
25 mg/kg
Twice daily, for the duration of the study
To evaluate the effect of SR1001 on the EAE model, results showed that SR1001 delayed the onset and clinical severity of EAE and suppressed the mRNA expression of Il17a, Il21, and Il22 in the spinal cord.
Nature. 2011 Apr 28;472(7344):491-4
Wistar rats
Chronic restraint stress model
Intraperitoneal injection
25 mg/kg
Daily for 28 days
SR1001 treatment significantly ameliorated CRS-induced depressive-like behavior in the sucrose preference test, forced swim test, and novelty-suppressed feeding test. Additionally, SR1001 reduced the expression levels of IL-6, IL-17, and IL-22 in serum.
J Neuroinflammation. 2022 Jul 14;19(1):186
BALB/c mice
House dust mite (HDM)-induced allergic airway inflammation model
Intraperitoneal injection
25 mg/kg
Twice daily, for a total of five times
SR1001 significantly reduced the proportion of proinflammatory Mo-AMs in the bronchoalveolar lavage fluid (BALF) of mice and decreased immune cell infiltration and goblet cell hyperplasia in lung tissue.
Front Immunol. 2024 May 28;15:1408772
Mice
LDL-R−/− mice
Intraperitoneal injection
25 mg/kg
Twice daily for one month
SR1001 treatment significantly reduced plaque formation, decreased plasma low-density lipoprotein (LDL) levels without affecting high-density lipoprotein (HDL). Additionally, SR1001 induced an anti-atherogenic immune profile characterized by a reduction in Th17 cells and an increase in Treg and Th2 cells.
Mol Metab. 2016 Jul 25;5(10):997-1005
Mice
LDL-R−/− mice
Intraperitoneal injection
25 mg/kg
Twice daily for one month
SR1001 treatment significantly decreased plaque formation, reduced plasma LDL levels without affecting HDL, and modulated cholesterol metabolism by increasing intestinal cholesterol excretion. Additionally, SR1001 induced an anti-atherogenic immune profile characterized by a reduction in Th17 cells and an increase in Treg and Th2 cells.
Mol Metab. 2016 Jul 25;5(10):997-1005
C57BL/6 mice
CLP-induced sepsis-associated pancreatic injury model
Intraperitoneal injection
25 mg/kg
Once daily for three days
To investigate the protective effect of SR1001 on sepsis-associated pancreatic injury, results showed that SR1001 significantly alleviated pancreatic injury and inhibited the RhoA/ROCK1 pathway.
Heliyon. 2023 Sep 18;9(9):e20118
Mice
STZ-induced diabetic mouse model
Subcutaneous injection
5 μM/100 μL
Once per week for 2 months or 8 months
SR1001 treatment significantly reduced retinal inflammation, oxidative stress, and capillary degeneration in diabetic mice, and decreased leukocyte adhesion and retinal endothelial cell death.
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