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. Our recent results show that IFN-gamma dependent induction of Mig and Crg-2 genes can occur in nonlymphoid organs, and these genes are rapidly induced in purified hepatocytes isolated from mice treated with IL-12 plus IL-2, or from Hepa 1-6 hepatoma cells treated in vitro with IFN gamma. The upregulation of hepatocyte-associated Mig and Crg-2 gene expression is accompanied by the coordinate upregulation of the alpha and beta components of the IFN gamma receptor. Supernatants of primary hepatocytes from IL-12/IL-2 treated mice, or from hepatocytes treated in vitro with IFN gamma, are chemotactic for both T and NK cells. The T cell, but not NK cell, chemoattracting activity was completely ablated by antibodies specific for Mig and Crg-2. These results suggest that cross-talk between parenchymal cells and leukocytes in some organs may be important for the initiation and/or amplification of inflammatory or antitumor responses. The results may also provide insight into mechanisms by which the innate and adaptive immune systems interface for the development of anti-tumor and inflammatory responses.
