TOXIC METALS STIMULATE INFLAMMATORY CYTOKINES IN HEPATOCYTES THROUGH OXIDATIVE STRESS MECHANISMS

Hepatocytes, as well as nonparenchymal cells, secrete proinflammatory cytokines and chemokines that are involved in the pathology of many li ver diseases. In particular, tumor necrosis factor-alpha (TNF alpha), as well as members of the CXC family of chemokines, including interleu kin (IL)-8 in humans and macrophage inflammatory protein (MIP)-2 in ro dents, have been implicated in both damage and repair processes associ ated with various hepatotoxins. In the liver, cytokine secretion is us ually associated with nonparenchymal cells, particularly Kupffer cells . In the present studies, cytokine gene expression and secretion were investigated in hepatocytes treated with cadmium chloride (CdCl2) or v anadium pentoxide (V2O5). Using human Hep G2 cells and freshly isolate d rodent hepatocytes, it was demonstrated that metals increase gene ex pression and secretion of CXC chemokines and TNF alpha. IL-8 and MIP-2 secretion induced either by the metals or H2O2 were inhibited by anti oxidants such as tetramethyl-thiourea and N-acetyl-cysteine. In vitro neutralization experiments with TNF alpha and in vivo studies with TNF alpha receptor knockout mice indicated that the metals directly stimu late CXC chemokine secretion without the need for TNF alpha. Taken tog ether these studies indicate that, in addition to other inflammatory m ediators and acute phase proteins, cytokines and chemokines are produc ed by hepatocytes, which may participate in hepatotoxic responses. The events responsible for their expression involve cellular redox change s.