Induction of lipocalin-2 expression in acute and chronic experimental liver injury moderated by pro-inflammatory cytokines interleukin-1ß through nuclear factor-κB activation.

BACKGROUND: Lipocalin-2 (LCN2) belongs to the lipocalin superfamily, sharing a barrel-shaped tertiary structure with a hydrophobic pocket and an ability to bind lipophilic molecules. LCN2 has recently emerged as an important modulator of cellular homeostasis in several organs, i.e. heart, lung and kidney, but little is known about the expression of LCN2 in acute and chronic liver injury. AIMS: In this study, we wanted to analyse the expression and regulation of LCN2 in models of acute and chronic experimental liver injury. MATERIALS AND METHODS: We analysed LCN2 expression in livers of rats subjected to bile duct ligation or repeated doses of carbon tetrachloride and tested the impact of various pro-inflammatory cytokines in cultured primary liver cells. RESULTS: By using primary cultures of hepatic stellate cells and hepatocytes isolated from normal and injured rat livers, we found a significant LCN2 expression in early hepatic stellate cell cultures, a lower expression in fully transdifferentiated myofibroblasts and no expression in freshly isolated hepatocytes. However, LCN2 expression and secretion in hepatocytes increased dramatically during culturing. In addition, chronic in vivo liver injury resulting from both bile duct ligation and repeated application of carbon tetrachloride resulted in rapid and well-sustained induction of LCN2 expression. Immunohistochemistry and primary liver cell isolation identified injured hepatocytes as the main source of LCN2 production. LCN2 is strongly induced in both primary hepatocytes and immortalized hepatocellular carcinoma cell line HepG2 by the pro-inflammatory cytokine interleukin-1ß via nuclear factor-κB activation, but not by the profibrotic cytokines platelet-derived growth factor and transforming growth factor-ß. CONCLUSION: LCN2 expression shows clear correlation to liver damage and resulting inflammatory responses, rather than to the degree of liver fibrosis, which in fact may imply a distinct diagnostic value as an early biomarker of liver inflammation.

Disruption of the latent transforming growth factor-beta binding protein-1 gene causes alteration in facial structure and influences TGF-beta bioavailability.

Latent transforming growth factor-beta binding proteins are a family of extracellular matrix proteins comprising four isoforms (LTBP-1, -2, -3, -4) with different structures, tissue expression patterns and affinity for TGF-beta. So far, respective knockout models have highlighted some essential functions for LTBP-2, LTBP-3 and LTBP-4, while the physiological significance of LTBP-1 is only superficially known. Here we report for the first time the generation and characterization of a mouse model lacking both the long and short LTBP-1 isoform. Surprisingly, respective mice are viable and fertile. However, detailed X-ray analysis of the skull revealed a modified facial profile. In addition, the gene disruption induces a reduced biological activity of TGF-beta that became evident in an experimental model of hepatic fibrogenesis in which the LTBP-1 knockout animals were less prone to hepatic fibrogenesis. Furthermore, comparative cDNA microarray gene expression profiling of cultured hepatic stellate cells confirmed that respective nulls were less receptive to cellular activation and transdifferentiation into myofibroblasts. Therefore, we conclude that LTBP-1 has essential functions in the control of TGF-beta activation.