The laboratory is principally involved in the study of receptor signal transduction for several growth factors and the identification of receptors that share subunits or are members of the same receptor superfamily. These growth factors primarily have effects on cells of lymphoid and hematological origin or as in the case of prolactin, breast tissue normal and transformed. The laboratory has extended its investigations into the role of the JAK/Stat pathway for specific cytokine receptors. AG-490 is a member of the tyrphostin familly of tyrosine kinase inhibitors. While originally considered to be a JAK 2 specific inhibitor from studies drawn from acute lymphoblastic leukemia cells, our studies have clearly shown that AG-490 potently suppresses cytokine responses that activate JAK 3. Accordingly, AG-490 inhibits the cytokine activites of IL-2, IL-4,IL-7, IL-9,and IL-15. As such, downstream transcription factors are blocked from activation and essential growth genes are not promoted. Thus, the AG-490 remains a potent immune inhibitor which, when used in animal studies, blocks graft vs host disease and rejection of some allografts. The relationship between cytokine signaling and other steroid hormone signals has only recently been investigated. We have found that a newly described nuclear receptor ppar gamma interferes with T cell activation related gene transcripition. The activated ppar gamma receptor physically complexes with the T cell transcription factor NFAT. The physical association blocks NFAT from translocating to the nucleus and cooperating with other transcrption factor on the IL-2 promoter. IL-2 transcription is potently blocked. Cross-talk between cytokine signaling and steroid receptor-signaling has also been studied in a prostate cancer model. IL-6 rapidly promotes the growth of certain human prostate cancer cell lines. IL-6 acts in a manner which apparently activates the androgen receptor (AR) in the absence of the androgen steroid.The AR is activated in a unique steroid-independent manner which involves a complex formation between STAT3 and AR. STAT3, a transcription factor which is tyrosine phosphorylated by JAK 2, in response to IL-6 receptor activation, associates with the AR and causes the activation of AR dependent gene transcription. This represents a novel mechanism whereby immune mediators and inflammatory molecular may promote certain tumors usurping the steroid hormone control mechanisms. Cytokine signaling steroid receptor cross-talk has also been studied in human multiple myeloma cell lines. Interestingly, all MM cell lines examined to date express estrogen receptors. Many MM cell produce significant quantities of IL-6 and respond in an autocrine proliferative manner. The addition of synthetic estrogens to cultures of MM cells induces significant apoptosis or programmed cell death. The activated ER appears to complex with the STAT3 transcription factor and prevent its transcriptional functions. This functionally blocks the molecular transcription function activated by IL-6 and activates the expression of apoptic gene function. The interaction of steriod nuclear receptors clearly act as modifiers by biological responses controlled by cytokines.
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