Liver Nonparenchymal Cells Are Stimulated to Provide Interleukin 6 for Induction of the Hepatic Acute-Phase Response in Endotoxemia but Not in Remote Localized Inflammation

Abstract

It has been postulated that Kupffer cells provide signals that regulate hepatocyte responses in sepsis and inflammation. Although in vitro data support such a hypothesis, to our knowledge, no in vivo evidence has been reported. We injected rats with lipopolysaccharide intraperitoneally to simulate sepsis or turpentine intramuscularly to mimic localized inflammation. Both treatments are known to induce the hepatic acute-phase response. Liver nonparenchymal cells and hepatocytes were isolated and placed in culture. Hepatocyte fibrinogen synthesis was measured as an indication of interleukin 6 exposure, while nonparenchymal interleukin 6 production was measured directly. Both lipopolysaccharide and turpentine stimulated a sharp increase in hepatocyte fibrinogen synthesis (turpentine greater than lipopolysaccharide). However, only lipopolysaccharide injection was associated with increased nonparenchymal cell interleukin 6 synthesis. Increased circulating levels of interleukin 6 could be found only after lipopolysaccharide injection. In addition, tumor necrosis factor synthesis was enhanced by lipopolysaccharide but not turpentine. Our data show that nonparenchymal cells are stimulated to provide the interleukin 6 signal to hepatocytes in endotoxemia but not in remote localized inflammation, even though both treatments stimulate the hepatic acute-phase response. Our findings support paracrine functions for liver sinusoidal cells in certain septic states.

Distinct Roles of Hepatocyte- and Myeloid Cell-Derived IL-1 Receptor Antagonist during Endotoxemia and Sterile Inflammation in Mice

“…Several cell types, particularly myeloid cells, are known to produce IL-1b and IL-6 in response to LPS. For example, it was reported that liver Küpfer cells are stimulated to provide the IL-6 signal to hepatocytes during endotoxemia (40). Consistent with these different observations, we observed elevated levels of IL-1b and IL-6 in the circulation and liver of LPS-treated mice (data not shown).…”

Suppression of Drug-Metabolizing Enzymes and Efflux Transporters in the Intestine of Endotoxin-Treated Rats

“…However, there is increasing evidence that the intestinal mucosa responds to endotoxin in a manner similar to the well characterized hepatic acute phase response (Molmenti et al, 1993;Wang et al, 1998). Endotoxin is known to stimulate the production of IL-6 in liver (Billiar et al, 1992). Indeed, we observed an increased expression of IL-6 mRNA in the intestinal segments of LPS-treated rats that is consistent with that reported by Wang et al (1998).…”

A microfluidically perfused three dimensional human liver model

“…Kupffer cells are specialized tissue macrophages that represent 15% of total liver cells and almost 80e90% of all tissue macrophages in the body [2]. Macrophages are key regulators of inflammatory response during infection and the major source of inflammatory cytokines such as interleukin (IL)-6 driving acute phase protein production in hepatocytes [3,4]. However, macrophages as well as hepatic stellate cells (HSCs) also mediate tissue regeneration in response to druginduced liver damage [5], regulate the complex balance of inflammation and tissue regeneration [6,7], and facilitate cellecell communication between hepatocytes and endothelial cells (ECs) [8].…”