Rapamycin alleviates inflammation by up-regulating TGF-β/Smad signaling in a mouse model of autoimmune encephalomyelitis.
10.12122/j.issn.1673-4254.2019.01.06
- Author:
Zhenfei LI
1
;
Lingling NIE
2
;
Liping CHEN
1
;
Yafei SUN
1
;
Li GUO
1
Author Information
1. Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang 050000, China.
2. Shijiazhuang Circulating Chemical Park Hospital, Shijiazhuang 050000, China.
- Publication Type:Journal Article
- Keywords:
Smad2;
Smad3;
Treg cells;
experimental autoimmune encephalomyelitis;
multiple sclerosis
- MeSH:
Animals;
Anti-Inflammatory Agents;
administration & dosage;
therapeutic use;
Cell Differentiation;
drug effects;
Encephalomyelitis, Autoimmune, Experimental;
drug therapy;
metabolism;
Interferon-gamma;
metabolism;
Interleukins;
metabolism;
Lymphocytes;
cytology;
Mice;
Mice, Inbred C57BL;
Sirolimus;
administration & dosage;
therapeutic use;
Smad Proteins;
metabolism;
T-Lymphocytes, Regulatory;
cytology;
drug effects;
Transforming Growth Factor beta;
metabolism;
Up-Regulation
- From:
Journal of Southern Medical University
2019;39(1):35-42
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVE:To evaluate the efficacy of rapmycin for treatment of experimental autoimmune encephalomyelitis (EAE) in mice and explore the underlying mechanism.
METHODS:An EAE model was established in C57BL/6 mice. After immunization, the mice were divided into model group and rapamycin groups treated daily with low-dose (0.3 mg/kg) or high-dose (1 mg/kg) rapamycin. The clinical scores of the mice were observed using Knoz score, the infiltration of IL-17 cells in the central nervous system (CNS) was determined using immunohistochemistry; the differentiation of peripheral Treg cells was analyzed using flow cytometry, and the changes in the levels of cytokines were detected with ELISA; the changes in the expressions of p-Smad2 and p- smad3 were investigated using Western blotting.
RESULTS:High-dose rapamycin significantly improved the neurological deficits scores of EAE mice. In high-dose rapamycin group, the scores in the onset stage, peak stage and remission stage were 0.14±0.38, 0.43±1.13 and 0.14±0.37, respectively, as compared with 1.14±0.69, 2.14±1.06 and 2.2±0.75 in the model group. The infiltration of inflammatory IL-17 cells was significantly lower in high-dose rapamycin group than in the model group (43±1.83 153.5±7.02). High-dose rapamycin obviously inhibited the production of IL-12, IFN-γ, IL-17 and IL-23 and induced the anti-inflammatory cytokines IL-10 and TGF-β. The percentage of Treg in CD4+ T cells was significantly higher in high- dose rapamycin group than in the model group (10.17 ± 0.68 3.52 ± 0.32). In the experiment, combined treatments of the lymphocytes isolated from the mice with rapamycin and TGF-β induced a significant increase in the number of Treg cells (13.66±1.89) compared with the treatment with rapamycin (6.23±0.80) or TGF-β (4.87±0.85) alone. Rapamycin also obviously up-regulated the expression of p-Smad2 and p-Smad3 in the lymphocytes.
CONCLUSIONS:Rapamycin can promote the differentiation of Treg cells by up-regulating the expression of p-Smad2 and p-smad3 to improve neurological deficits in mice with EAE.
