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

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.

Serum growth differentiation factor 15 level is associated with muscle strength and lower extremity function in older patients with cardiometabolic disease

“…GDF15 is upregulated in many tissues in response to inflammation and may reduce the activation of proinflammatory factors, consequently inhibiting the activation of nuclear factor-κB. 26 The activation of mTORC1 by aging or pathological conditions may increase the expression of GDF15 and STAT3's phosphorylation in skeletal muscles, which could then induce oxidative stress and catabolic changes in skeletal muscle. 27 GDF15 has also been implicated in mitochondrial dysfunction, which may play an essential role in muscle dysfunction through the loss of ATP (adenosine triphosphate) production, reduced oxidative phosphorylation, deregulation of the ubiquitin-proteasome pathway, decrease in mitochondrial biogenesis, endoplasmic reticulum stress, mitophagy, modification of mitochondrial DNA and increased mitochondrial oxidative stress in skeletal muscle.…”

Isorhamnetin Inhibits Liver Fibrosis by Reducing Autophagy and Inhibiting Extracellular Matrix Formation via the TGF-β1/Smad3 and TGF-β1/p38 MAPK Pathways

“…Our previous study also showed that IH inhibited hepatocyte apoptosis and autophagy induced by inflammation, thereby improving liver function [20]. It indicated that the hepatoprotective role of IH could be attributed to the anti-inflammation effect [41, 42].…”

Tumor necrosis factor α in aGVHD patients contributed to the impairment of recipient bone marrow MSC stemness and deficiency of their hematopoiesis-promotion capacity

“…Though the data above have demonstrated the pivotal role of TNF-α in aGVHD-mediated BM damage, the molecular mechanisms underlying TNF-α control of the stemness and hematopoiesis-promoting capacity of MSCs need to be further clarified. In the current study, the comprehensive results of a high-throughput RNA sequencing analysis suggested that numerous genes including ICAM-1, IL-1β, BMP4, and GDF15 may be responsible for the special mechanisms of TNF-α mediated effects of stem cell properties [34][35][36][37][38]. The further GO annotation revealed the biological process of the differential abundant genes.…”