Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), along with its receptor fibroblast growth factor-inducible (Fn)14, is associated with various biological activities including inflammation. However, its role in the pathogenesis of Graves’ orbitopathy (GO) is unknown. In this study, we investigated the mechanism by which TWEAK regulates inflammatory signaling in orbital fibroblasts from GO patients. We found that TWEAK and tumor necrosis factor-α (TNFA) mRNA levels were upregulated in GO as compared to non-GO tissue samples. TWEAK, TNF receptor (TNFR)1, TNFR2, and TNFR superfamily member 12A mRNA, and TWEAK and Fn14 protein levels were increased by interleukin (IL)-1β and TNF-α treatment. Treatment with exogenous recombinant TWEAK increased the transcript and protein expression of the pro-inflammatory cytokines IL-6, IL-8, and monocyte chemoattractant protein-1 to a greater extent in GO than in non-GO cells, while treatment with the anti-Fn14 antibody ITEM4 suppressed TWEAK-induced pro-inflammatory cytokine release and hyaluronan production. Additionally, the serum level of TWEAK was higher in Graves’ disease patients with (341.86 ± 86.3 pg/ml) as compared to those without (294.09 ± 41.44 pg/ml) GO and healthy subjects (255.33 ± 39.38 pg/ml), and was positively correlated with clinical activity score (r = 0.629, P < 0.001) and thyroid binding immunoglobulin level (r = 0.659, P < 0.001). These results demonstrate that TWEAK/Fn14 signaling contributes to GO pathogenesis. Moreover, serum TWEAK level is a potential diagnostic biomarker for inflammatory GO, and modulating TWEAK activity may be an effective therapeutic strategy for suppressing inflammation and tissue remodeling in GO.
Bibliographical noteFunding Information:
This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (NRF-2017R1A2B4009565). JSY received the grant. (www.nrf.re.kr). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
© 2018 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)
- Agricultural and Biological Sciences(all)