IFN-γ deficiency attenuates hepatic inflammation and fibrosis in a steatohepatitis model induced by a methionine- and choline-deficient high-fat diet

Abstract

Cytokines play important roles in all stages of steatohepatitis, including hepatocyte injury, the inflammatory response, and the altered function of sinusoidal cells. This study examined the involvement of a major inflammatory cytokine, interferon-γ (IFN-γ), in the progression of steatohepatitis. In a steatohepatitis model by feeding a methionine- and choline-deficient high-fat (MCDHF) diet to both wild-type and IFN-γ-deficient mice, the liver histology, expression of genes encoding inflammatory cytokines, and fibrosis-related markers were examined. To analyze the effects of IFN-γ on Kupffer cells in vitro, we examined the tumor necrosis factor-α (TNF-α) production by a mouse macrophage cell line. Forty two days of MCDHF diet resulted in weight loss, elevated aminotransferases, liver steatosis, and inflammation in wild-type mice. However, the IFN-γ-deficient mice exhibited less extensive changes. RT-PCR revealed that the expression of tumor necrosis factor-α (TNF-α), transforming growth factor-β, inducible nitric oxide synthase, interleukin-4 and osteopontin were increased in wild-type mice, although they were suppressed in IFN-γ-deficient mice. Seventy days of MCDHF diet induced much more liver fibrosis in wild-type mice than in IFN-γ-deficient mice. The expression levels of fibrosis-related genes, α-smooth muscle actin, type I collagen, tissue inhibitor of matrix metalloproteinase-1, and matrix metalloproteinase-2, were dramatically increased in wild-type mice, whereas they were significantly suppressed in IFN-γ-deficient mice. Moreover, in vitro experiments showed that, when RAW 264.7 macrophages were treated with IFN-γ, they produced TNF-α in a dose-dependent manner. The present study showed that IFN-γ deficiency might inhibit the inflammatory response of macrophages cells and subsequently suppress stellate cell activation and liver fibrosis. These findings highlight the critical role of IFN-γ in the progression of steatohepatitis.

Quantitative Proteomic analysis on Activated Hepatic Stellate Cells reversion Reveal STAT1 as a key regulator between Liver Fibrosis and recovery

“…Furthermore, in our down-regulated proteomic list, ISG20 and Mx1 protein, related to IFN signaling pathway, could be activated by STAT1. Moreover, IFN-γ deficiency could inhibit the inflammatory response of Kupffer cells, subsequently suppress HSCs activation and liver fibrosis35. Collectively, these experiments highlighted the critical role of STAT1 in the progression of liver fibrosis and indicated that suppression of STAT1 promote the reversion of activated HSCs.…”

Iron overload results in hepatic oxidative stress, immune cell activation, and hepatocellular ballooning injury, leading to nonalcoholic steatohepatitis in genetically obese mice

“…In our model, iron appears to be the trigger to cause the switch in polarization toward the M1 macrophages. In addition, CD8 T cells, which are one of the main producers of the potent cytokine, interferon ␥, were upregulated in the DI mice and have been implicated in the mechanisms leading to NASH (19,28). Additionally, DCs, a type of antigen-presenting myeloid immune cell population (characterized by the presence of CD11c marker, which was elevated in the livers of the DI mice), have also been proposed to contribute to the pathogenic process that governs NASH (12).…”

The osteopontin transgenic mouse is a new model for Sjögren's syndrome

“…Similar to IL-2, IL-4 and Opn were both elevated in liver tissue in a steatohepatitis model [58, 59]. While it is known that stimulation of B cells with IL-4 along with B-cell receptor engagement results in Opn production [6], the effect of Opn on IL-4 production is less clear.…”