Jung-Yoon Choe1, Seung-Jin Lee, Sung-Hoon Park, Seong-Kyu Kim. 1. Department of Internal Medicine, Arthritis and Autoimmunity Research Center, Catholic University of Daegu School of Medicine, 3056-6 Daemyung 4-Dong, Namgu, Daegu 705-718, Republic of Korea.
Abstract
OBJECT: This study aimed to identify the regulatory effect of tacrolimus on the interleukin-1β (IL-1β)-induced expressions of angiopoietin-1 (Ang-1), Tie-2 receptor (Tie-2), and vascular endothelial growth factor (VEGF) in human rheumatoid fibroblast-like synoviocytes (FLS) and to determine the regulatory mechanism in the mitogen-activated protein kinases (MAPKs) signaling pathway. METHODS: IL-1β-induced Ang-1, Tie-2, and VEGF expressions with and without tacrolimus were measured in cultured FLS using real time-polymerase chain reaction, enzyme-linked immunosorbent assay, Western blotting, and immunofluorescence staining. The effect of tacrolimus on the regulation of Ang-1, Tie-2 and VEGF expressions through the MAPK signaling pathway was identified by Western blotting and immunofluorescence staining. RESULTS: IL-1β appeared to induce marked expressions of Ang-1, Tie-2, and VEGF in cultured FLS. Tacrolimus significantly inhibited Ang-1, Tie-2, and VEGF mRNA and protein in cultured FLS treated with 10 ng/ml IL-1β. In addition, expressions of these angiogenic molecules were shown to involve all three of the studied MAPK signaling pathways, including ERK, JNK, and p38. However, the inhibitory effects of tacrolimus on Ang-1, Tie-2, and VEGF proteins were regulated by blocking the phosphorylations of JNK and p38 MAPK, but not that of ERK. CONCLUSION: This study demonstrates that tacrolimus inhibits the expressions of Ang-1, Tie-2, and VEGF by blocking the activations of the IL-1β-mediated JNK and p38 MAPK pathways in human FLS. This suggests that tacrolimus contributes to the suppression of angiogenesis in the pathogenesis of RA. Copyright Â
OBJECT: This study aimed to identify the regulatory effect of tacrolimus on the interleukin-1β (IL-1β)-induced expressions of angiopoietin-1 (Ang-1), Tie-2 receptor (Tie-2), and vascular endothelial growth factor (VEGF) in humanrheumatoid fibroblast-like synoviocytes (FLS) and to determine the regulatory mechanism in the mitogen-activated protein kinases (MAPKs) signaling pathway. METHODS: IL-1β-induced Ang-1, Tie-2, and VEGF expressions with and without tacrolimus were measured in cultured FLS using real time-polymerase chain reaction, enzyme-linked immunosorbent assay, Western blotting, and immunofluorescence staining. The effect of tacrolimus on the regulation of Ang-1, Tie-2 and VEGF expressions through the MAPK signaling pathway was identified by Western blotting and immunofluorescence staining. RESULTS: IL-1β appeared to induce marked expressions of Ang-1, Tie-2, and VEGF in cultured FLS. Tacrolimus significantly inhibited Ang-1, Tie-2, and VEGF mRNA and protein in cultured FLS treated with 10 ng/ml IL-1β. In addition, expressions of these angiogenic molecules were shown to involve all three of the studied MAPK signaling pathways, including ERK, JNK, and p38. However, the inhibitory effects of tacrolimus on Ang-1, Tie-2, and VEGF proteins were regulated by blocking the phosphorylations of JNK and p38MAPK, but not that of ERK. CONCLUSION: This study demonstrates that tacrolimus inhibits the expressions of Ang-1, Tie-2, and VEGF by blocking the activations of the IL-1β-mediated JNK and p38MAPK pathways in human FLS. This suggests that tacrolimus contributes to the suppression of angiogenesis in the pathogenesis of RA. Copyright Â
Authors: Hwa Jin Jang; Konstantin Tsoyi; Young Min Kim; Eun Jung Park; Sang Won Park; Hye Jung Kim; Jae Heun Lee; Ki Churl Chang Journal: Br J Pharmacol Date: 2013-03 Impact factor: 8.739