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Joint Bone Spine
Volume 79, n° 2
pages 137-143 (mars 2012)
Doi : 10.1016/j.jbspin.2011.03.018
accepted : 23 Mars 2011
Tacrolimus (FK506) inhibits interleukin-1β-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
 

Jung-Yoon Choe a, b, Seung-Jin Lee b, Sung-Hoon Park a, b, Seong-Kyu Kim a, , b
a 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 
b Arthritis and Autoimmunity Research Center, Catholic University of Daegu, Daegu, Republic of Korea 

Corresponding author. Tel.: +82 53 6503038; fax: +82 53 6298248.
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 10ng/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.

The full text of this article is available in PDF format.

Keywords : Rheumatoid arthritis, Tacrolimus, Angiopoietin-1, Tie-2 receptor, Vascular endothelial growth factor




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