Expression and Regulation of Cell Adhesion Molecules by Hepatic Stellate Cells (HSC) of Rat Liver

Abstract

Hepatic stellate cells (HSC), a pericyte-like nonparenchymal liver cell population, are regarded as the principal matrix-synthesizing cells of fibrotic liver. They might also play a role during liver inflammation. The present study analyzed (i) expression of cell adhesion molecules (CAMs) mediating cell infiltration, like intercellular adhesion molecule-1 (I-CAM-1) and vascular cell adhesion molecule-1 (V-CAM-1), by HSC, (ii) CAM regulation in HSC by growth factors and inflammatory cytokines, and (iii) CAM expression in situ during liver inflammation, using immunochemistry and Northern blot analysis. I-CAM-1 and V-CAM-1 expression was present in HSC in vitro and in cells located in the sinusoidal/perisinusoidal area of normal liver. Growth factors, eg, transforming growth factor-beta1, down-regulated I-CAM-1- and V-CAM-1-coding mRNAs and stimulated N-CAM expression of HSC. In contrast, inflammatory cytokines like tumor necrosis factor-alpha reduced N-CAM-coding mRNAs, whereas induction of I-CAM-1- and V-CAM-1-specific transcripts increased several fold. In situ, messengers specific for I-CAM-1 and V-CAM-1 were induced 3 hours after CCl4 treatment (thereby preceding mononuclear cell infiltration starting at 12 hours), were expressed at maximal levels 9-12 hours after CCl4 application, and decreased afterwards. I-CAM-1 and V-CAM-1 immunoreactivity increased in a linear fashion starting 3 hours after CCl4-induced liver injury, was detected in highest amounts at 24-48 hours characterized by maximal cell infiltration, and returned to baseline values at 96 hours. Interestingly, the induction/repression of CAM-specific messengers paralleled the time kinetics of tumor necrosis factor-alpha transforming growth factor-beta1 expression in injured liver. HSC might be important during the onset of hepatic tissue injury as proinflammatory elements and might interact with I-CAM-1 and V-CAM-1 ligand-bearing cells, namely lymphocyte function-associated antigen-1- or Mac-1/very late activation antigen-4-positive inflammatory cells, thereby modulating the recruitment and migration of mononuclear cells within the perisinusoidal space of diseased livers.

Localization of liver myofibroblasts and hepatic stellate cells in normal and diseased rat livers: distinct roles of (myo-)fibroblast subpopulations in hepatic tissue repair

“…4), but also at 48 h after CCl 4 application (data not shown), an increase in the number of either GFAP-or desmin-positive cells was evident in the necrotic area compared to uninjured tissue regions in accordance with previous studies (Knittel et al , 1999aNeubauer et al 1996). The same was true in the case of V-CAM-1, however one has to take into consideration that apart from HSC other cells, such as sinusoidal endothelial cells and Kupffer cells, might be labeled (Knittel et al 1999a). A semiquantitative analysis comparing the amount of desmin-, GFAP-, or V-CAM-1-positive cells in injured versus uninjured tissue areas was performed at different time points after CCl 4 application.…”

“…In accordance with published data HSC, identified by the presence of GFAP, desmin, or V-CAM-1, were detected in the hepatic parenchyma within the perisinusoidal space (Knittel et al , 1999aNeubauer et al 1996; Fig. 1; Table 1).…”

“…Furthermore, desmin was also detectable in the portal field within the walls of the hepatic artery or the portal vein and the portal interstitium (Table 1). V-CAM-1-specific staining reactions were additionally present in a sinusoidal pattern in the parenchyma due to its expression by other sinusoidal liver cells, such as endothelial cells or Kupffer cells (Knittel et al 1999a).…”

Pathogenic Roles of Tumor Necrosis Factor Receptor p55–Mediated Signals in Dimethylnitrosamine-Induced Murine Liver Fibrosis

“…Activated HSCs express ␣-SMA, vimentin, or fibronectin (Friedman, 1993;Knittel et al, 1999a). Several lines of evidence demonstrate that HSCs are activated by several cytokines or growth factors, including TNF-␣ and TGF-␤ (Armendariz-Borunda et al, 1992;Czaja et al, 1989;Hellerbrand et al, 1996Hellerbrand et al, , 1998Knittel et al, 1996Knittel et al, , 1997Knittel et al, , 1999bSaile et al, 1999). Although TNF-␣ has also been described to down-regulate the expression of the Type I collagen genes in human fibroblasts and rat HSCs in vitro by directly antagonizing fibrogenic actions of TGF-␤ at the transcriptional level (ArmendarizBorunda et al, 1992;Iraburu et al, 2000;Solis-Herruzo et al, 1988), the current observations suggest that TNF-␣-mediated and/or TNFRp55-mediated signals may contribute to the activation of HSC and eventually the promotion of fibrotic changes in the liver.…”

Peroxisome Proliferator-activated Receptor γ Induces a Phenotypic Switch from Activated to Quiescent Hepatic Stellate Cells

“…Sustained NF-B activation confers activated HSC their proliferative and antiapoptotic status that may be important in progressive liver fibrogenesis (5). NF-B may also mediate inflammatory responses by HSC via induction of chemokines and adhesion molecules (6,7). Increased activator protein-1 (AP-1) activity is essential for induction of matrix metalloproteinase (8), tissue inhibitor of matrix metalloproteinase-1, and interleukin-6 (9) gene transcription in activated HSC, where JunD is shown to play a pivotal role (9).…”