Kupffer cells
The most important function of Kupffer cells is defense against infections and tumor cells. Kupffer cells act as antigen presenting cells and as effector cells that act directly by phagocytosis, or indirectly by activation of other cells, e.g. NK cells. Though Kupffer cells are constantly acting as scavengers, they can be activated through different pathways. Firstly, soluble mediators can trigger their activation. IFN-γ is the prototypical macrophage activating factor. It is central to the development of Th1-dominated immune responses, and it affects not only macrophages in an autocrine fashion, but other immune cells as well.One of the key events during innate immune reactions is the production of IL-12, mainly by macrophages. IL-12 induces NK cells to rapidly secrete IFN-γ, which then in turn activates macrophages early in the immune response. It also induces IFN-γ production by T cells. IL- 18, which is produced by Kupffer cells and other cell types, is also involved in enhancing IFN-γ production by T cells. Macrophages also secrete IFN-γ upon stimulation with IL-12 and IL-18 together. It is known that IFN-γ is a possible reducer of metastasis of colon cancer in the liver. Macrophages can also be activated by direct interaction with micro-organisms or bacterial products such as lipopoly-saccharide, glucan, muramyl dipeptide and lipid A[52]. A pivotal role for IFN-γ in the clearance of various intracellular pathogens has been amply demonstrated. It has been described that macrophages release the cytotoxic radical, NO. In vitro studies suggested that NO induces mitochondrial dysfunction in tumor cells followed by membrane barrier dysfunction in the liver sinusoid. Another important cytotoxic factor released by activated macrophages is tumor necrosis factor alpha (TNF-α), which is produced in both soluble and membrane-bound forms. After binding to its receptor, apoptosis can be induced in the target cell.Cytotoxicity of macrophages can be classified into antibody-dependent and antibody-independent cell-mediated cytotoxicity. Both pathways are contact dependent and induce tumor cell death after a number of hours. Antibody-dependent cell-mediated cytotoxicity is based on the recognition of an antibody-coated target by Fc receptors on the effector cells. Upon cross-linking of the Fc receptor, secretion of cytotoxic mediators occurs. Secretion of reactive oxygen species, IL-1 and TNF-α are probably involved. Antibody-independent cell-mediated cytotoxicity involves binding to the macrophage followed by translocation of the lysosomal organelles to the target. Moreover, cytotoxicity towards tumor targets involves cytolysis and phagocytosis.In certain pathophysiologic conditions, apoptosis is chaotic and non-selective, may be massive and occurs persistently over an extended period of time. A large number of apoptotic bodies produced are phagocytosed by Kupffer cells. It has recently been reported that engulfment of apoptotic bodies results in the generation of death ligands, such as FasL and TNF-α on the membrane of the Kupffer cells, but engulfment of latex beads does not produce a similar response. This means that uptake of apoptotic bodies induces an additional immunologic response involving liver inflammation and fibrosis.
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