| First Author | Yang X | Year | 2018 |
| Journal | Sci Rep | Volume | 8 |
| Issue | 1 | Pages | 188 |
| PubMed ID | 29317674 | Mgi Jnum | J:264490 |
| Mgi Id | MGI:6148596 | Doi | 10.1038/s41598-017-18380-0 |
| Citation | Yang X, et al. (2018) Spred2 Deficiency Exacerbates D-Galactosamine/Lipopolysaccharide -induced Acute Liver Injury in Mice via Increased Production of TNFalpha. Sci Rep 8(1):188 |
| abstractText | Acute liver injury (ALI) is characterized by hepatocyte damage and inflammation. In the present study, we examined whether the absence of Sprouty-related EVH1-domain-containing protein 2 (Spred2), a negative regulator of the Ras/Raf/ERK/MAPK pathway, influences ALI induced by D-galactosamine (D-GalN) and lipopolysaccharide (LPS). Compared to wild-type mice, Spred2(-/-) mice developed exacerbated liver injury represented by enhanced hepatocyte damage and inflammation. Enhanced ERK activation was observed in Spred2(-/-)-livers, and the MEK/ERK inhibitor U0126 ameliorated ALI. Hepatic tumour necrosis factor alpha (TNFalpha) and interleukin (IL)-1beta levels were increased in Spred-2(-/-)-livers, and the neutralization of TNFalpha dramatically ameliorated ALI, which was associated with decreased levels of endogenous TNFalpha and IL-1beta. When mice were challenged with D-GalN and TNFalpha, much severer ALI was observed in Spred2(-/-) mice with significant increases in endogenous TNFalpha and IL-1beta in the livers. Immunohistochemically, Kupffer cells were found to produce TNFalpha, and isolated Kupffer cells from Spred2(-/-) mice produced significantly higher levels of TNFalpha than those from wild-type mice after LPS stimulation, which was significantly decreased by U0126. These results suggest that Spred2 negatively regulates D-GalN/LPS-induced ALI under the control of TNFalpha in Kupffer cells. Spred2 may present a therapeutic target for the treatment of ALI. |
