Tumor necrosis factor-like weak inducer of apoptosis induces inflammation in Graves’ orbital fibroblasts

Abstract

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.

Comparative transcriptome analysis of human and murine choroidal neovascularization identifies fibroblast growth factor inducible-14 as phylogenetically conserved mediator of neovascular age-related macular degeneration

“…Blocking the FN14-TWEAK-pathway resulted in a significant reduction of IL-6 concentration in the CNV microenvironment with a tendency to also decrease IL-33, CXCL2 and CCL5, although the differences were not significant. These results are in accordance with studies on human astrocytes (Saas et al, 2000) and orbital fibroblasts (Lee et al, 2018) as well as murine synovial (Kamata et al, 2006) and mesangial cells (Campbell et al, 2006), which have shown FN14-TWEAK activation to induce IL-6, CXCL2 and CCL5 secretion, respectively. These results may indicate that FN14 influences CNV development, at least in part, through modulation of IL-6, although this does not exclude other soluble factors to be regulated by the treatment with the FN14 decoy receptor.…”

Comparative transcriptome analysis of human and murine choroidal neovascularization identifies fibroblast growth factor inducible-14 as phylogenetically conserved mediator of neovascular age-related macular degeneration

“…Blocking the FN14-TWEAK-pathway resulted in a significant reduction of IL-6 concentration in the CNV microenvironment with a tendency to also decrease IL-33, CXCL2 and CCL5, although the differences were not significant. These results are in accordance with studies on human astrocytes (Saas et al, 2000) and orbital fibroblasts (Lee et al, 2018) as well as murine synovial (Kamata et al, 2006) and mesangial cells (Campbell et al, 2006), which have shown FN14-TWEAK activation to induce IL-6, CXCL2 and CCL5 secretion, respectively. These results may indicate that FN14 influences CNV development, at least in part, through modulation of IL-6, although this does not exclude other soluble factors to be regulated by the treatment with the FN14 decoy receptor.…”

Chronic inflammation: key player and biomarker-set to predict and prevent cancer development and progression based on individualized patient profiles

“…And these factors promote proliferation and differentiation of epithelial cells and endothelial cells [105], then might induce cancers. Lee et al found TNF-like weak inducer induced inflammation with real-time polymerase chain reaction (RT-PCR), western blotting, and enzyme-linked immunosorbent assay (ELISA) [106]. Khodabandehlon et al found the existence of human papillomavirus was related to tumor progress and the increase of inflammatory cytokines (IL-6, IL-17, IL-1, NF-κB, TNF-α, and TGF-β) with ELISA and RT-PCR [107].…”