Ruiru Li1, Haobo Lin2, Yujin Ye1, Youjun Xiao1, Siqi Xu1, Jingnan Wang1, Cuicui Wang1, Yaoyao Zou1, Maohua Shi1, Liuqin Liang1, Hanshi Xu3. 1. Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, PR China. 2. Department of Rheumatism, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, PR China. 3. Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, PR China. Electronic address: xuhanshi@mail.sysu.edu.cn.
Abstract
OBJECTIVE: Hydroxychloroquine (HCQ) is an antimalarial drug that is widely used in the treatment of some autoimmune diseases. In the present study, we explore the role of HCQ in regulating endothelial inflammation and its underlying mechanism. METHODS: Human umbilical vein endothelial cells (HUVECs) were isolated from fresh umbilical cords. Protein expression was measured by Western blot or immunofluorescence staining. Endothelial adhesion ability was determined by leukocyte-endothelial monolayer adhesion assay. Transwell assay was used to measure the transendothelial-migration of PBMCs. RESULTS: TNF-α-induced endothelial-leukocyte adhesion and the leukocyte transmigration were profoundly reduced by HCQ treatment. HCQ treatment dramatically inhibited the expression of TNF-α-induced endothelial ICAM-1 and VCAM-1. Furthermore, treatment with HCQ prevented the TNF-α-induced translocation of NF-κB p65 into the nucleus and the phosphorylation of the p65 subunit in HUVECs. HCQ inhibited the expression of phosphorylated p38 and JNK protein but not ERK. Treatment with NF-κB, p38 and JNK inhibitor could also reduce TNF-α-induced endothelial-leukocyte adhesion and the endothelial expression of ICAM-1 and VCAM-1. HCQ administration also suppressed TNF-α induced lung injury in mice by reducing neutrophil infiltration in pulmonary interstitial tissue. CONCLUSIONS: This work shows the inhibitory effect of HCQ on endothelial inflammatory response through, at least in part, blocking NF-κB, p38 and JNK pathways. Our findings suggest that HCQ may be a promising approach for the treatment of inflammatory vascular disease beyond its immunomodulatory actions.
OBJECTIVE:Hydroxychloroquine (HCQ) is an antimalarial drug that is widely used in the treatment of some autoimmune diseases. In the present study, we explore the role of HCQ in regulating endothelial inflammation and its underlying mechanism. METHODS:Human umbilical vein endothelial cells (HUVECs) were isolated from fresh umbilical cords. Protein expression was measured by Western blot or immunofluorescence staining. Endothelial adhesion ability was determined by leukocyte-endothelial monolayer adhesion assay. Transwell assay was used to measure the transendothelial-migration of PBMCs. RESULTS: TNF-α-induced endothelial-leukocyte adhesion and the leukocyte transmigration were profoundly reduced by HCQ treatment. HCQ treatment dramatically inhibited the expression of TNF-α-induced endothelial ICAM-1 and VCAM-1. Furthermore, treatment with HCQ prevented the TNF-α-induced translocation of NF-κB p65 into the nucleus and the phosphorylation of the p65 subunit in HUVECs. HCQ inhibited the expression of phosphorylated p38 and JNK protein but not ERK. Treatment with NF-κB, p38 and JNK inhibitor could also reduce TNF-α-induced endothelial-leukocyte adhesion and the endothelial expression of ICAM-1 and VCAM-1. HCQ administration also suppressed TNF-α induced lung injury in mice by reducing neutrophil infiltration in pulmonary interstitial tissue. CONCLUSIONS: This work shows the inhibitory effect of HCQ on endothelial inflammatory response through, at least in part, blocking NF-κB, p38 and JNK pathways. Our findings suggest that HCQ may be a promising approach for the treatment of inflammatory vascular disease beyond its immunomodulatory actions.
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