GDF‑15 prevents LPS and D‑galactosamine‑induced inﬂammation and acute liver injury in mice

Li,Min; Song,Kui; Huang,Xiaowen; Fu,Simao; Zeng,Qiyi

doi:10.3892/ijmm.2018.3747

GDF‑15 prevents LPS and D‑galactosamine‑induced inﬂammation and acute liver injury in mice

Authors:
- Min Li
- Kui Song
- Xiaowen Huang
- Simao Fu
- Qiyi Zeng
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Affiliations: Department of Pediatrics, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China, Department of Hematology, The First Affiliated Hospital of Jishou University, Jishou, Hunan 416000, P.R. China, Department of Pediatrics, Boai Hospital of Zhongshan City, Zhongshan, Guangdong 528400, P.R. China, Department of Pediatrics, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
Published online on: June 27, 2018 https://doi.org/10.3892/ijmm.2018.3747
Pages: 1756-1764

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Abstract

Growth differentiation factor‑15 (GDF‑15) is a transforming growth factor (TGF)‑β superfamily member with a poorly characterized biological activity, speculated to be implicated in several diseases. The present study aimed to determine whether GDF‑15 participates in sepsis‑induced acute liver injury in mice. Lipopolysaccharide (LPS) and D‑galactosamine (D‑GalN) were administered to mice to induce acute liver injury. Survival of mice, histological changes in liver tissue, and levels of inflammatory biomarkers in serum and liver tissue were evaluated following treatment with GDF‑15. The underlying mechanism was investigated by western blotting, ELISA, flow cytometry, and reverse transcription‑quantitative polymerase chain reaction using Kupffer cells. The results demonstrated that GDF‑15 prevented LPS/D‑GalN‑induced death, increase in inflammatory cell infiltration and serum alanine aminotransferase and aspartate aminotransferase activities. In addition, GDF‑15 treatment reduced the production of hepatic malondialdehyde and myeloperoxidase, and attenuated the increase of interleukin (IL)‑6, tumor necrosis factor (TNF)‑α, and IL‑1β expression in serum and liver tissue, accompanied by inducible nitric oxide synthase (iNOS) inactivation in the liver. Similar changes in the expression of inflammatory cytokines, IL‑6, TNF‑α and IL‑1β, and iNOS activation were observed in the Kupffer cells. Further mechanistic experiments revealed that GDF‑15 effectively protected against LPS‑induced nuclear factor (NF)‑κB pathway activation by regulating TGFβ‑activated kinase 1 (TAK1) phosphorylation in Kupffer cells. In conclusion, GDF‑15 reduced the activation of pro‑inflammatory factors, and prevented LPS‑induced liver injury, most likely by disrupting TAK1 phosphorylation, and consequently inhibiting the activation of the NF‑κB pathway in the liver.

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