Benzylideneacetophenone derivatives attenuate IFN-gamma-induced IP-10/CXCL10 production in orbital fibroblasts of patients with thyroid-associated ophthalmopathy through STAT-1 inhibition.
- Author:
Sung Hee LEE
1
;
Seul Ye LIM
;
Ji Ha CHOI
;
Jae Chul JUNG
;
Seikwan OH
;
Koung Hoon KOOK
;
Youn Hee CHOI
Author Information
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords: benzylideneacetophenone; CXCL10/IP-10; IFN-gamma; orbital fibroblasts; thyroid-associated ophthalmopathy; yakuchinone B
- MeSH: 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
- From:Experimental & Molecular Medicine 2014;46(6):e100-
- CountryRepublic of Korea
- Language:English
- 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)-gamma-induced protein (IP)-10/CXCL10 production in these cells was determined. IFN-gamma strongly increased the level of IP-10/CXCL10 in orbital fibroblasts from patients with TAO. JC3 exerted a significant inhibitory effect on the IFN-gamma-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-gamma-induced production of IP-10/CXCL10. JC3 significantly attenuated the IP-10/CXCL10 mRNA expression induced by IFN-gamma, and a gel-shift assay showed that JC3 suppressed IFN-gamma-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-gamma 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.
