Benzylideneacetophenone derivatives attenuate IFN-γ-induced IP-10/CXCL10 production in orbital fibroblasts of patients with thyroid-associated ophthalmopathy through STAT-1 inhibition.

Abstract

The aim of the present study was to identify a new candidate anti-inflammatory compound for use in the active stage of thyroid-associated ophthalmopathy (TAO). Benzylideneacetophenone compound JC3 [(2E)-3-(4-hydroxy-3-methoxyphenyl)phenylpro-2-en-l-one] was synthesized based on a structural modification of yakuchinone B, a constituent of the seeds of Alpinia oxyphylla, which belongs to the ginger family (Zingiberaceae), has been widely used in folk medicine as an anti-inflammatory phytochemical. Orbital fibroblasts were primarily cultured from patients with TAO, and the potential of JC3 to suppress the interferon (IFN)-γ-induced protein (IP)-10/CXCL10 production in these cells was determined. IFN-γ strongly increased the level of IP-10/CXCL10 in orbital fibroblasts from patients with TAO. JC3 exerted a significant inhibitory effect on the IFN-γ-induced increase in IP-10/CXCL10 in a dose-dependent manner; its potency was greater than that of an identical concentration of yakuchinone B with no toxicity to cells at the concentration range used. Moreover, the constructed dimer and trimer polystructures of JC3, showed greater potency than JC3 in suppressing the IFN-γ-induced production of IP-10/CXCL10. JC3 significantly attenuated the IP-10/CXCL10 mRNA expression induced by IFN-γ, and a gel-shift assay showed that JC3 suppressed IFN-γ-induced DNA binding of signal transducer and activator of transcription-1 (STAT-1) in TAO orbital fibroblasts. Our results provide initial evidence that the JC3 compound reduces the levels of IP-10/CXCL10 protein and mRNA induced by IFN-γ in orbital fibroblasts of TAO patients. Therefore, JC3 might be considered as a future candidate for therapeutic application in TAO that exerts its effects by modulating the pathogenic mechanisms in orbital fibroblasts.

• Authors: Sung-Hee Lee, Seul Ye Lim, Ji Ha Choi, Jae-Chul Jung, Seikwan Oh, Koung Hoon Kook, Youn-Hee Choi
• Journal: Experimental & molecular medicine (Exp Mol Med) Vol. 46 Pg. e100 (Jun 13 2014) ISSN: 2092-6413 [Electronic] United States
• PMID: 24924312 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CXCL10 protein, human
• Chemokine CXCL10
• Diarylheptanoids
• RNA, Messenger
• STAT1 Transcription Factor
• STAT1 protein, human
• yakuchinone B
• Chalcone
• Interferon-gamma

Topics

• Cells, Cultured
• Chalcone (chemical synthesis, pharmacology)
• Chemokine CXCL10 (genetics, metabolism)
• Diarylheptanoids (chemistry, pharmacology)
• Fibroblasts (drug effects, metabolism)
• Graves Ophthalmopathy (metabolism)
• Humans
• Interferon-gamma (metabolism)
• Orbit (cytology)
• RNA, Messenger (genetics, metabolism)
• STAT1 Transcription Factor (genetics, metabolism)