INTERLEUKIN-4 AND THEIR RECEPTORS IN TUMOR BIOLOGY AND AIDS

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We have discovered that a variety of human solid tumor cells express Interleukin-4 Receptors (IL-4R). Studies were carried out to characterize the functional significance and structure of IL-4R on human solid and hematologic tumors, IL-4R directed targeting of a Pseudomonas exotoxin (PE), and regulation and interaction of IL- 4R with other cytokines. 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. Crosslinking studies were carried out which demonstrated that IL-4R on renal cell carcinoma (RCC) tumor cells is composed of one predominant protein of about 140 kDa compared to H-9 T cell lymphoma and Raji B cell Burkitt~s lymphoma cells which in addition to the140 kDa band also expressed a smaller 70 kDa protein. We also discovered that IL-2R g chain may be possibly associated with IL-4R on RCC cells. Northern analysis, however, demonstrated that g chain mRNA is absent in RCC cells while it is strongly expressed in B and T lyphoma cells. Experiments in progress aim to determine the identity of this novel IL-4R associated protein on RCC cells.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. Newer generations of IL4-PE toxins were also produced which bound IL-4R better than old IL4-toxin. In addition, this chimeric protein was more cytotoxic to IL-4R positive tumor cells; however, normal peripheral blood lymphocytes were somewhat resistant to the cytotoxic effect. Anit- tumor studies were carried out in nude mice using older toxin in a xenograft model bearing human epidermoid carcinoma. Our data demonstrat that IL4-PE4E and IL4-PE38QQR, two chimeric toxins, caused the regression of established human tumor xenografts in mice. Complete regressions were observed although transient. Studies are underway to explore optimal route and schedule of therapy and type of human tumor which will be most susceptible to the antitumor effect of IL4-toxins. C. Mechanism of IL- 4R regulation by HIV-tat gene. The internalization and recycling of IL- 4R complex was similar in both tat transfected and untransfected Raji cells. The half life of IL-4R protein after cycloheximide treatment does not appear to alter due to tat transfection. Similarly, actinomycin chase experiments demonstrated that the half life of IL-4R mRNA is similar in both types of cells. In contrast, preliminary nuclear run-off experiments demonstrated that the tat gene may increase the transcription rate of IL- 4R in Raji cells. These results suggest that IL-4R upregulation by the tat gene is mediated through an increase in transcription rate of IL-4R.