Peptide-Based TNF-α-Binding Decoy Therapy Mitigates Lipopolysaccharide-Induced Liver Injury in Mice.

Chao-Yuan Chang,Hung-Jen Shih,Jossen Foo,Chun-Jen Huang,Hao-Jen Hsu

doi:10.3390/ph13100280

Chao-Yuan Chang, Hung-Jen Shih + Show 3 more

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https://doi.org/10.3390/ph13100280

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Abstract

A peptide named SEM18, possessing structural similarity to the binding site of tumor necrosis factor (TNF)-α to TNF receptor 1 (TNFR1), was designed. We investigated whether the SEM18 peptide can mitigate lipopolysaccharide (LPS)-induced liver injury in mice. Adult male Balb/cJ mice received LPS (15 mg/kg; LPS group) or LPS plus SEM18 (LSEM group). Control groups were run simultaneously. At 2 h after LPS, the first dose of SEM18 (0.3 mg/kg) was administered, followed by three supplemental doses of SEM18 (0.15 mg/kg, every 2 h). At 24 h after LPS, surviving mice were euthanized for analyses. Compared with the LPS group, binding of TNF-α to TNFR1 in liver tissues was significantly lower in the LSEM group (p < 0.001). Plasma concentrations of aspartate transaminase and alanine transaminase, as well as Suzuki’s scores (liver damage assessment), wet/dry weight ratios, levels of polymorphonuclear neutrophil infiltration, and levels of mitochondrial injury in liver tissues, of the LSEM group were significantly lower than in the LPS group (all p < 0.05). Levels of necroptosis, pyroptosis, apoptosis, and autophagy upregulation in liver tissues in the LSEM group were also significantly lower than in the LPS group (all p < 0.05). Notably, exogenous TNF-α counteracted these effects of SEM18. SEM18 peptide mitigates LPS-induced liver injury in mice.

Highlights

Tumor necrosis factor-α (TNF-α), a 17 kDa protein and a pleiotropic cytokine, is derived mainly from infectious stimulus-activated immune cells via a Toll-like receptor (TLR)/nuclear factor-κB (NF-κB) pathway during sepsis [1]
These data demonstrated that organ injuries mediated by tumor necrosis factor (TNF)-α and the tumor necrosis factor-α (TNF-α)/TNF receptor 1 (TNFR1) pathway during sepsis may involve mitochondrial injury/dysfunction and upregulation of the cell death processes of necroptosis, pyroptosis, apoptosis, and autophagy
The plasma concentrations of SEM18 peptide were determined via measuring biotin concentrations in plasma using enzyme-linked immunosorbent assay (ELISA)

Summary

Introduction

Tumor necrosis factor-α (TNF-α), a 17 kDa protein and a pleiotropic cytokine, is derived mainly from infectious stimulus-activated immune cells (e.g., macrophages) via a Toll-like receptor (TLR)/nuclear factor-κB (NF-κB) pathway during sepsis [1]. Autophagy is a process of self-degradation, and crosstalk between autophagy and various processes of cell death has been highlighted [14] These data demonstrated that organ injuries mediated by TNF-α and the TNF-α/TNFR1 pathway during sepsis may involve mitochondrial injury/dysfunction and upregulation of the cell death processes of necroptosis, pyroptosis, apoptosis, and autophagy. These data further highlighted that TNF-α and TNFR1 can be novel therapeutic targets against sepsis

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