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DIRECT AND INDIRECT MECHANISMS FOR REGULATION OF HUMAN HEPATIC ACUTE PHASE GENE EXPRESSION

Several distinct and well-characterized cytokines can mediate fever and changes in metabolism characteristic of the host response to inflammation/injury. In this study, the cytokines interleukin-1 (IL-1), cachectin/tumor necrosis factor (TUP) and interferon-γ (TFNγ), acting on human hepatoma cells (HepG2, Hep3B), directly mediated changes in expression of several plasma proteins, characteristic of the acute phase response. Recombinant human IL-1β or TNFα increased steady state levels of mRNA for and rate of synthesis of complement proteins C3, factor B, α-1-antichymotrypsin and decreased steady state levels of mRNA for and rate of synthesis of albumin and transferrin in HepG2 and Hep3B cells. Recombinant human IFNγ increased steady state levels of mRNA for and rate of synthesis of IL-l- and TNF-unresponsive complement protein Ch. Recombinant human IL-2 also elicited hepatic acute phase gene expression but through an indirect pathway involving the induction of monocyte IL-l release. The effect of these cytokines on hepatic acute phase genes (factor B, C4) was also evident in mouse fibroblasts transfected with the cloned human factor B or C4 genes suggesting the presence of regulatory elements within the gene or its flanking regions. These results indicate that the human hepatic acute phase response can be studied in a human hepatoma cell with the use of well-characterized and highly purified cytokines. In vivo, hepatic acute phase gene expression is likely to involve several different mediators acting through several pathways.