title: 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.affiliation: 1] Department of Physiology and Global Top5 Research Program, Ewha Woman's University School of Medicine, Seoul, Korea [2] Tissue Injury Defense Research Center, Ewha Woman's University School of Medicine, Seoul, Korea.
authors.forename: Sung-Hee
authors.initials: SH
authors.lastname: Lee
authors.affiliation: 1] Department of Physiology and Global Top5 Research Program, Ewha Woman's University School of Medicine, Seoul, Korea [2] Tissue Injury Defense Research Center, Ewha Woman's University School of Medicine, Seoul, Korea.
authors.forename: Seul Ye
authors.initials: SY
authors.lastname: Lim
authors.affiliation: 1] Tissue Injury Defense Research Center, Ewha Woman's University School of Medicine, Seoul, Korea [2] Department of Pharmacology, Ewha Woman's University School of Medicine, Seoul, Korea.
authors.forename: Ji Ha
authors.initials: JH
authors.lastname: Choi
authors.affiliation: 1] Tissue Injury Defense Research Center, Ewha Woman's University School of Medicine, Seoul, Korea [2] Department of Neuroscience, Ewha Woman's University School of Medicine, Seoul, Korea.
authors.forename: Jae-Chul
authors.initials: JC
authors.lastname: Jung
authors.affiliation: 1] Tissue Injury Defense Research Center, Ewha Woman's University School of Medicine, Seoul, Korea [2] Department of Neuroscience, Ewha Woman's University School of Medicine, Seoul, Korea.
authors.forename: Seikwan
authors.initials: S
authors.lastname: Oh
authors.affiliation: Department of Ophthalmology, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Koung Hoon
authors.initials: KH
authors.lastname: Kook
authors.affiliation: 1] Department of Physiology and Global Top5 Research Program, Ewha Woman's University School of Medicine, Seoul, Korea [2] Tissue Injury Defense Research Center, Ewha Woman's University School of Medicine, Seoul, Korea.
authors.forename: Youn-Hee
authors.initials: YH
authors.lastname: Choi
mesh_terms: D002478:Cells, Cultured; D002599:Chalcone / Q000138:chemical synthesis / Q000494:pharmacology*; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism*; D036381:Diarylheptanoids / Q000737:chemistry / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D049970:Graves Ophthalmopathy / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D009915:Orbit / Q000166:cytology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D036381:Diarylheptanoids; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C121978:yakuchinone B; D002599:Chalcone; D007371:Interferon-gamma