Tacrolimus (FK506) inhibits interleukin-1尾-induced angiopoietin-1, Tie-2 receptor, and vascular endothelial growth factor through down-regulation of JNK and p38 pathway in human rheumatoid fibroblast-like synoviocytes

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• 作者：Jung-Yoon Choe^a ; ^b ; Seung-Jin Lee^b ; Sung-Hoon Park^a ; ^b ; Seong-Kyu Kim^a ; ^b ; ^{kimsk714@cu.ac.kr}
• 关键词：Rheumatoid arthritis ; Tacrolimus ; Angiopoietin-1 ; Tie-2 receptor ; Vascular endothelial growth factor
• 刊名：Joint Bone Spine
• 出版年：2012
• 期刊代码：138_1297319x
• 类别：med
• 出版时间：March, 2012
• 卷：79
• 期：2
• 页码：137-143
• 文件大小：489 K

摘要

Object

This study aimed to identify the regulatory effect of tacrolimus on the interleukin-1尾 (IL-1尾)-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-1尾-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-1尾 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-1尾. 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-1尾-mediated JNK and p38 MAPK pathways in human FLS. This suggests that tacrolimus contributes to the suppression of angiogenesis in the pathogenesis of RA.