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

Sung Jun Lee, Jinjoo Kim, Jae Sang Ko, Eun Jig Lee, Hyoung Jun Koh, Jin Sook Yoon

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article numbere0209583
JournalPloS one
Volume13
Issue number12
DOIs
Publication statusPublished - 2018 Dec

Fingerprint

tumor necrosis factors
Tumor Necrosis Factor Receptors
Fibroblasts
fibroblasts
cytokines
pathogenesis
apoptosis
Tumor Necrosis Factor-alpha
inflammation
Receptors, Tumor Necrosis Factor, Type II
Tissue
Apoptosis
Cytokines
Inflammation
hyaluronic acid
Fibroblast Growth Factor Receptors
Messenger RNA
receptors
Chemokine CCL2
interleukin-8

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

@article{e39f9a645c334deaa72f883dc0a0604e,
title = "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.",
author = "Lee, {Sung Jun} and Jinjoo Kim and Ko, {Jae Sang} and Lee, {Eun Jig} and Koh, {Hyoung Jun} and Yoon, {Jin Sook}",
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journal = "PLoS One",
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Tumor necrosis factor-like weak inducer of apoptosis induces inflammation in Graves’ orbital fibroblasts. / Lee, Sung Jun; Kim, Jinjoo; Ko, Jae Sang; Lee, Eun Jig; Koh, Hyoung Jun; Yoon, Jin Sook.

In: PloS one, Vol. 13, No. 12, e0209583, 12.2018.

Research output: Contribution to journalArticle

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