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)-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.