We have discovered that a variety of human solid tumor cells express Interleukin-4 Receptors (IL-4R). In addition, IL-4R are upregulated by HIV regulatory gene tat on human Burkitt's lymphoma (Raji) cell line. Studies were carried out to characterize: A. the functional significance and structure of IL-4R on human solid and hematologic tumors; B. IL-4R directed targeting of a Pseudomonas endotoxin (PE); C. Mechanism of IL-4R regulation by HIV-tat gene. A. Structure and Function of IL-4 receptors on tumor cells. IL-4 caused the inhibition of tumor cell growth in tissue culture and this inhibition was of different degrees in different human tumors. In contrast, IL-4 caused modest stimulation of growth in normal human endothelial and fibroblast cell lines. Human renal cell carcinoma (RCC) cells were most susceptible to the growth inhibitory effects of IL-4. Experiments are in progress to determine other functions of IL-4R (e.g. regulation of HLA antigens, IL-4R, and cytokine production) on these tumor cells. In preliminary experiments, IL-4R structure and properties appear to be similar in both RCC and human B cell derived lymphoma cell line. In both cell types IL-4R appear to be internalized and recycled. Structure of IL- 4R and possibility of association of other subunit(s) to IL-4R is being explored by cross linking and immunoprecipitation experiments using anti- IL-4R antibodies. B. IL-4R directed targeting of a Pseudomonas exotoxin. The IL-4R expressed on human tumor cells were targeted with a chimeric protein comprised of IL-4 and PE. This protein was highly cytotoxic to IL-4R positive tumor cells, however, normal cells e.g. peripheral blood lymphocytes, endothelial cells and fibroblasts were somewhat resistant to the cytotoxic effect of IL4-PE. Studies are underway to examine anti- tumor properties of this chimeric protein against a variety of human cancers.
