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.

Differential responses of innate immunity triggered by different subtypes of influenza a viruses in human and avian hosts

“…Among all the different chemokine (C-X-C motif) ligands, CXCL10 was found to be up-regulated most extensively. Previous studies showed the up-regulation of CXCL10 in several cell types and in response to different pro-inflammatory molecules, always in conjunction with IFN-γ (Type II IFN) [ 48 – 50 ]. However, our results suggest that the increase in the production of CXCL10 may be independent with IFN-γ in HTBE cells during the course of influenza A virus infection.…”

Autoimmune thyroid disorders

“…Further studies are needed to evaluate whether CXCL10 is a novel therapeutic target in HT, GD and GO [78,79].…”

The aggregation between AITD with rheumatologic, or dermatologic, autoimmune diseases

“…Therefore, the detection of high level of CXCL10, CXCL9 in peripheral fluids is a marker of a Th1 orientated-immune response (85). However, more investigations are needed to evaluate whether IFN-γ dependent chemokines are new therapeutic targets in HT, GD and GO (96,97). IFN-γ dependent chemokines serum and tissue expressions are increased in systemic rheumatologic or dermatologic disorders; this underlined the importance of a shared immune-pathogenesis of these pathologies, in which is mainly present a predominant autoimmune response Th1-related in the initial, and/or in their active phases (86,98,99).…”