ABSTRACT
Previous studies have consistently demonstrated that dopamine D1-like receptor (D1-like-R) signalling is implicated in the pathogenesis of experimental autoimmune encephalomyelitis and type I diabetes. Given that allergic asthma shares certain disease aetiology similarities with autoimmune diseases, we conducted studies in OVA-induced mice aiming to address the impact of D1-like-R signalling on the pathogenesis of allergic asthma. It was noted that blockade of D1-like-R signalling provided protection for mice against OVA-induced acute asthma. Particularly, treatment of OVA-induced mice with SCH23390, a D1-like-R antagonist, significantly attenuated inflammatory infiltration in the airways along with repressed goblet cell hyperplasia and mucus production, as well as airway resistance. By contrast, administration of SKF83959, a D1-like-R agonist, displayed the opposite effect. Blockade of D1-like-R signalling impaired Th17 function, as manifested by a significant reduction of Th17 cells in the spleen and bronchoalveolar lavage fluid. Mechanistic studies revealed that D1-like-R signalling enhances B-cell activating transcription factor activity, which then transcribes the expression of RORγt, a Th17 transcription factor; accordingly, D1-like-R signalling regulates Th17 differentiation to promote the development of allergic asthma. Taken together, the data obtained in the present suggest that blockade of D1-like-R signalling could be an effective therapeutic strategy for the prevention and treatment of allergic asthma in clinical practice.
Subject(s)
Asthma/prevention & control , Basic-Leucine Zipper Transcription Factors/antagonists & inhibitors , Benzazepines/pharmacology , Ovalbumin/toxicity , Receptors, Dopamine D1/antagonists & inhibitors , Th17 Cells/drug effects , Acute Disease , Animals , Asthma/chemically induced , Asthma/metabolism , B-Lymphocytes/drug effects , B-Lymphocytes/metabolism , B-Lymphocytes/pathology , Basic-Leucine Zipper Transcription Factors/genetics , Basic-Leucine Zipper Transcription Factors/metabolism , Blotting, Western , Bronchoalveolar Lavage Fluid , Cell Differentiation/drug effects , Cell Proliferation/drug effects , Dopamine/metabolism , Enzyme-Linked Immunosorbent Assay , Female , Flow Cytometry , Immunoenzyme Techniques , Lung/cytology , Lung/drug effects , Lung/metabolism , Mice , Mice, Inbred BALB C , RNA, Small Interfering/genetics , Th17 Cells/cytology , Th17 Cells/metabolismABSTRACT
Objective To investigate the effects of simvastatin on the production of interleukin (IL)-17and B-cell activating transcription factor (BATF) in the peripheral blood mononuclear cells (PBMCs) of rheumatoid arthritis (RA) patients and healthy individuals.Methods PBMCs were isolated from heparinized blood of healthy donors or RA patients using Ficoll-Hypaque density gradient centrifugation.The cells were stimulated by PMA and ionomycin in the absence or presence of simvastatin or MVA at 37 ℃ 5％CO2.The mRAN level of IL-17,BATF and GAPDH was detected by RT-PCR; the protein level of IL-17 in supernatants was assayed by ELISA kit; and the protein level of BATF was detected by Western Blotting.The comparison between the two groups was carried out by paired-t test and Chi-square test was used for muhi-group comparison.Results PBMCs of healthy donors [(69.2±12.2) vs (8.1±2.2) pg/ml,P＜0.05; (76.6±14.7) vs (10.2±7.2) pg/ml,P＜0.05] and RA patients [(79.6±12.7) vs (15.8±5.8) pg/ml,P＜0.05; (90.3±9.7) vs (12.9±7.9) pg/ml,P＜0.05] were stimulated with PMA and ionomycin to produce high levels of IL-17.After treatment with simvastatin,the expression and secretion level of IL-17 in healthy controls and RA PBMCs were markedly decreased.The inhibition of simvastatin on the production of IL-17 was reversed by mevalonic acid (MVA),but no significant changes of BATF after treating with simvastatin.Conclusion Simvastatin inhibits the production of IL-17 in the PBMCs at gene and protein levels,which is not targeted at suppressing the expression of IL-17 transcription factor BATF.
