Dataset Information

Tumor Necrosis Factor (TNF) Receptor Expression Determines Keratinocyte Fate upon Stimulation with TNF-Like Weak Inducer of Apoptosis.

ABSTRACT: The interaction between tumor necrosis factor- (TNF-) like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible 14 (Fn14) regulates the fate of keratinocytes, depending on the relative expression of TNF receptor (TNFR) 1 or TNFR2. However, the precise mechanism underlying this TWEAK-mediated regulation remains unclear. The aim of this study was to provide comprehensive insight into the roles of Fn14, TNFR1/2, and other relevant molecules in the fate of keratinocytes. Further, we sought to elucidate the structural basis for the interaction of TWEAK and Fn14 in regulating cellular outcomes. Normal keratinocytes (mainly expressing TNFR1) and TNFR2-overexpressing keratinocytes were stimulated with TWEAK. Through immunoprecipitation and Western blotting of keratinocyte lysates, we elucidated the associations between Fn14, TNFR-associated factor 2 (TRAF2), cellular inhibitor of apoptosis protein 1 (cIAP1), and TNFR1/2 molecules. Additionally, we found that TRAF2 exhibited binding to Fn14, cIAP1, and TNFR1/2. Our data suggest that TWEAK induces apoptosis in normal keratinocytes and proliferation in TNFR2-overexpressing keratinocytes in a TNF-?-independent manner; however, inhibition of TRAF2 appears to reverse this effect. Interestingly, the interaction between TWEAK and Fn14 increased TNFR1-associated death domain protein and caspase-8 expression in normal keratinocytes and promoted cytoplasmic import of cIAP1 in TNFR2-overexpressing keratinocytes. In conclusion, we found that the Fn14-TRAF2-TNFR signaling axis mediates TWEAK's regulation of the fate of keratinocytes, possibly in a manner involving the TNF-?-independent TNFR signal transduction.

SUBMITTER: Wang X

PROVIDER: S-EPMC6915140 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Tumor Necrosis Factor (TNF) Receptor Expression Determines Keratinocyte Fate upon Stimulation with TNF-Like Weak Inducer of Apoptosis.

Wang Xuening X Cheng Dan D Hu Guanglei G Liang Lili L Tan Fei F Xiao Tong T Xiao Shengxiang S Xia Yumin Y

Mediators of inflammation 20191205

The interaction between tumor necrosis factor- (TNF-) like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible 14 (Fn14) regulates the fate of keratinocytes, depending on the relative expression of TNF receptor (TNFR) 1 or TNFR2. However, the precise mechanism underlying this TWEAK-mediated regulation remains unclear. The aim of this study was to provide comprehensive insight into the roles of Fn14, TNFR1/2, and other relevant molecules in the fate of keratinocytes. Further, ...[more]

PMID: 31885495

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Project description:To test the efficacy of TNFR-Fc and anti-TWEAK mAb treatment alone and in combination Tumor necrosis factor (TNF)-alpha is a major effector in various inflammatory conditions. TNF-like weak inducer of apoptosis (TWEAK) is a member of the TNF superfamily that promotes inflammatory tissue damage through its receptor, FGF-inducible molecule 14 (Fn14). Since both TWEAK and TNF-alpha have been shown to mediate pathological responses through inter-dependent or independent pathways by in vitro, the potential interplay of these pathways was investigated in a mouse colitis model. Acute colitis was induced by rectal injection of trinitrobenzene sulfonic acid (TNBS), with administration of control IgG, TNF receptor (TNFR)-Ig chimeric protein, anti-TWEAK monoclonal antibody, or the combination of TNFR-Ig and anti-TWEAK antibody. On day 4, disease severity was evaluated and gene expression profiling was analyzed using whole colon tissue. Levels of transcript of TWEAK, Fn14 and NF-kB-related molecules were measured in purified colon epithelial cells (ECs). NF-kB activation was investigated with Western blot and immunohistochemical analysis. As a result, activation of the canonical, but not noncanonical NF-kB pathway was the hallmark of inflammatory responses in this model. Inflammation induced upregulation of Fn14 only in ECs but not in other cell types. Combination treatment of TNFR-Ig and anti-TWEAK antibody synergistically reduced disease severity in comparison with the control antibody or single agent treatment. Gene expression profile of the colon indicated downregulation of canonical NF-kB pathway with combination treatment. In conclusion, synergistic activation of canonical NF-kB by TWEAK and TNF-alpha is critical for the induction of inflammatory tissue damage in acute inflammation. TNBS colitis was induced by intrarectal administration of a 2 % solution of TNBS in phosphate-buffered saline (PBS): ethanol (1:1). For acute inflammatory responses, 70 M-NM-<g/g body weight of TNBS was given on day 0 and animals sacrificed on day 4. One hour prior to administration of TNBS, groups of mice were injected i.p. with the control IgG2a mAb (anti-human CD20) (10 mg/kg), TNFR-Ig (0.3 mg/kg), anti-TWEAK (mP2D10, 10 mg/kg), the combination of TNFR-Fc (0.3 mg/kg) and anti-TWEAK mP2D10 (10 mg/kg), or were untreated. For single agent and combination treatments groups, 0.3 mg/kg TNFR-Ig was employed, since 1 mg/kg of TNFR-Ig markedly ameliorated TNBS colitis but 0.3 mg/kg was much less effective as monitored by the effect on colon length and body weight. Colon tissue was rolled and snap-frozen in liquid nitrogen. Specimens for RNA extraction were cut from the frozen rolled colon. A set of experiments using 5-8 mice for each experimental group was performed twice, labelled 7 and 10 in the CEL files. Total number of mice for each experimental condition was as follows; untreated TNBS colitis group, 8; control antibody, 15; TNFR-Ig, 12; anti-TWEAK mAb, 14; combination of TNFR-Ig and anti-TWEAK mAb, 15.

Dataset Information

Tumor Necrosis Factor (TNF) Receptor Expression Determines Keratinocyte Fate upon Stimulation with TNF-Like Weak Inducer of Apoptosis.

Publications

Tumor Necrosis Factor (TNF) Receptor Expression Determines Keratinocyte Fate upon Stimulation with TNF-Like Weak Inducer of Apoptosis.

Similar Datasets

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