In this project, the liver, lungs and kidneys are used as model organs to understand the mechanisms by which parenchymal cells and leukocytes communicate in different organ microenvironments. These studies have relevance to understanding the regulation and optimization of 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), NKT, and T cells, and they induce beneficial antitumor activities in numerous experimental models. IFN-gamma-dependent induction of the CXC chemokines Mig and Crg-2 can occur in many nonlymphoid organs including the liver and kidney. Recent results have implicated hepatocytes as a major contributor to the production of Mig and Crg-2 in the liver. More recently, we have also shown that IL-12 (pulse IL-2 induces strong induction of CXC chemokines in the kidney, which is a site for successful regression of tumors after treatment with IL-12 (pulse IL-2). We have also shown that IL-12/ pulse IL-2 immunotherapy has potent IFN-gamma-dependent anti-tumor effects against mouse renal cancer implanted into the kidney. An understanding of how kidney parenchymal and non-parenchymal cells participate in expression of CXC chemokines may be important for delineating relative contributions of these cells to inflammatory disease and anti-tumor responses in the kidney. A major goal of these studies is to determine if induction of non-ELR CXC chemokines by lipopolysaccharide (LPS), a combination of IL-12/pulse IL-2, and IFN-gamma use the same or different pathways. A second goal is to determine the relative participation of parenchymal vs non-parenchymal mesangial cells in expression of these chemokine genes. LPS, IFN-gamma and a combination of IL-12/pulse IL-2 all increased IP-10 and MIG message in kidney mesangial cells. LPS but not IL-12/pulse IL-2 was able to induce MIG and IP-10 gene expression in the kidneys of IFN-gamma -/- mice, demonstrating an IFN-gamma independent pathway. Furthermore, LPS and IL-12/pulse IL-2 induced MIG and IP-10 gene expression with different kinetics. LPS induced MIG and IP-10 message more rapidly, but with a shorter duration, than did IL-12/ pulse IL-2. Thus, the dependence of this process on IFN-gamma differs based on the nature of inflammation-inducing stimuli. These results suggest that both IFN-gamma dependent and independent pathways can be engaged in the kidney microenvironment and can contribute to local inflammation and/or cytokine mediated anti-tumor responses. The results further suggest that communication between parenchymal cells and leukocytes may be important for the development of inflammatory or antitumor responses.
