These studies use the liver as a model organ to understand the physiological mechanisms that regulate the development of innate immune responses and their relationship to metastasis formation and disease-induced inflammation. IL-12, IL-18 and IL-2 are potent immunoregulatory cytokines for natural killer (NK) and T cells, and they induce beneficial antitumor activities in numerous experimental models. The recruitment and regulation of several important leukocyte subsets(NK, NKT and T cells) in the liver is dependent on IFN-gamma, but the mechanisms by which these effects occur are not yet well understood.The IFN-gamma-inducible Mig and Crg-2 proteins can contribute to IL-12 and perhaps IL-18 induced anti-angiogenic and and leukocyte-recruiting activities, but the contributions of leukocytes versus parenchymal cells in different organs to the production of these molecules remains unclear. IFN-gamma-dependent induction of Mig and Crg-2 gene expression can occur in many nonlymphoid organs, and these genes are rapidly induced in purified hepatocytes isolated from mice treated with IL-2 + IL-12, or from Hepa 1-6 hepatoma cells treated in vitro with IFN-gamma. In addition to depending on IFN-gamma, the ability of IL-12 or IL-2/IL-12 to induce Mig and Crg-2 gene expression in purified hepatocytes also is accompanied by the coordinate upregulation of the IFN-gamma R alpha and beta-chains, in the absence of IL-12R components. Supernatants of primary hepatocytes obtained from mice treated in vivo with IL-2/IL-12 or from hepatocytes treated in vitro with IFN-gamma contain increased chemotactic activity for enriched human and mouse CD3+ T cells, as well as mouse DX5+ natural killer (NK) cells. The hepatocyte-derived chemotactic activity for mouse T cells, but not NK cells, was ablated by antibodies specific for Mig and Crg-2. These results suggest that parenchymal cells in some organs may contribute substantially to initiation and/or amplification of inflammatory or antitumor responses. These results suggest that communication between parenchymal cells and leukocytes may be important for the development of inflammatory or antitumor responses.
