Abstract
The liver is a central organ involved in inflammatory processes, including the elaboration of acute-phase proteins. Augmenter of liver regeneration (ALR) protein, expressed and secreted by hepatocytes, promotes liver regeneration and maintains viability of hepatocytes. ALR also stimulates secretion of inflammatory cytokines (tumor necrosis factor [TNF]-α and interleukin [IL]-6) and nitric oxide from Kupffer cells. We hypothesized that ALR may be involved in modulating inflammation induced by various stimuli. We found that hepatic ALR levels are elevated at 24 h, before or about the same time as an increase in the mRNA expression of TNF-α and IL-6, after portacaval shunt surgery in rats. Serum ALR also increased, but significantly only on d 4 when pathological changes in the liver become apparent. In rats, serum ALR was elevated after intraperitoneal administration of lipopolysaccharide alone and in a model of gram-negative sepsis. Serum ALR increased before alanine aminotransferase (ALT) in endotoxemia and in the same general time frame as TNF-α and IL-6 in the bacterial sepsis model. Furthermore, mathematical prediction of tissue damage correlated strongly with alterations in serum ALR in a mouse model of hemorrhagic shock. In vitro, monomethyl sulfonate, TNF-α, actinomycin D and lipopolysaccharide all caused increased release of ALR from rat hepatocytes, which preceded the loss of cell viability and/or inhibition of DNA synthesis. ALR may thus serve as a potential diagnostic marker of hepatocellular stress and/or acute inflammatory conditions.
Highlights
Augmenter of liver regeneration (ALR) is a novel protein, which was originally identified in the cytosolic fractions of the regenerating or hyperplastic liver [1]
We found that serum ALR levels increase in murine models of PCS, endotoxemia, sepsis and hemorrhagic shock, all before or in a similar time frame as the increase in inflammatory mediators or alanine aminotransferase (ALT)
The decrease in hepatic ALR corresponded to an increase in serum ALR, which was significant at 1 h, peaked at 3 h and remained elevated at 24 h
Summary
Found to cause progressive apoptosis and necrosis of the cells, which was accompanied by depletion of cellular ATP stores [3]. A G-protein–coupled receptor for ALR was identified on Kupffer cells, stimulation of which modestly increased the expression and release of tumor necrosis factor (TNF)-α, interleukin (IL)-6 and nitric oxide (NO) (via induction of inducible NO synthase) [9]. These mediators are ALR IN INFLAMMATION suggest that ALR is a novel inflammatory mediator or DAMP, given that DAMPs prototypically are produced in settings of injury, inflammation or stress and in turn promote further inflammation via induction of classic proinflammatory cytokines [19]
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