These authors contributed equally to this article.
Anti-arthritis effects of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal are mediated by inhibition of the STAT3 pathway
Article first published online: 15 MAY 2014
© 2014 The British Pharmacological Society
British Journal of Pharmacology
Volume 171, Issue 11, pages 2900–2912, June 2014
How to Cite
Ban, J. O., Kim, D. H., Lee, H. P., Hwang, C. J., Shim, J.-H., Kim, D. J., Kim, T. M., Jeong, H.-S., Nah, S. S., Chen, H., Dong, Z., Ham, Y. W., Kim, Y., Han, S.-B. and Hong, J. T. (2014), Anti-arthritis effects of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal are mediated by inhibition of the STAT3 pathway. British Journal of Pharmacology, 171: 2900–2912. doi: 10.1111/bph.12619
- Issue published online: 15 MAY 2014
- Article first published online: 15 MAY 2014
- Accepted manuscript online: 13 FEB 2014 12:40AM EST
- Manuscript Accepted: 28 JAN 2014
- Manuscript Revised: 16 DEC 2013
- Manuscript Received: 30 SEP 2013
- National Research Foundation of Korea (NRF)
- Korea government (MSIP). Grant Number: MRC,2008-0062275
- Ministry of Trade, Industry, & Energy (MOTIE. Grant Number: 141526993
- 4-bis(p-hydroxyphenyl)- 2-butenal;
Background and Purpose
Products of Maillard reactions between aminoacids and reducing sugars are known to have anti-inflammatory properties. Here we have assessed the anti-arthritis effects of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal and its possible mechanisms of action.
We used cultures of LPS-activated macrophages (RAW264.7 cells) and human synoviocytes from patients with rheumatoid arthritis for in vitro assays and the collagen-induced arthritis model in mice. NO generation, iNOS and COX2 expression, and NF-κB/IKK and STAT3 activities were measured in vitro and in joint tissues of arthritic mice, along with clinical scores and histopathological assessments. Binding of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal to STAT3 was evaluated by a pull-down assay and its binding site was predicted using molecular docking studies with Autodock VINA.
(E)-2,4-bis(p-hydroxyphenyl)-2-butenal (2.5–10 μg·mL−1) inhibited LPS-inducedNO generation, iNOS and COX2 expression, and NF-κB/IKK and STAT3 activities in macrophage and human synoviocytes. This compound also suppressedcollagen-induced arthritic responses in mice by inhibiting expression of iNOS and COX2, and NF-κB/IKK and STAT3 activities; it also reduced bone destruction and fibrosis in joint tissues. A pull-down assay showed that (E)-2,4-bis(p-hydroxyphenyl)-2-butenal interfered with binding of ATP to STAT3. Docking studies suggested that (E)-2,4-bis(p-hydroxyphenyl)-2-butenal bound to the DNA-binding interface of STAT3 possibly inhibiting ATP binding to STAT3 in an allosteric manner.
Conclusions and Implications
(E)-2,4-bis(p-hydroxyphenyl)-2-butenal exerted anti-inflammatory and anti-arthritic effects through inhibition of the NF-κB/STAT3 pathway by direct binding to STAT3. This compound could be a useful agent for the treatment of arthritic disease.