The laboratory has been involved in the study of cytokine signal transduction and cross-talk between steroid or non-steroid nuclear receptors and the transcription factors regulated by cytokines. (1) We have identified a novel non-steroid nuclear receptor, pparg,in human T lymphocytes and have studied its function. Activation of pparg by synthetic or endogenous ligands forms pparg complexes with the transcription factors NFAT and NF-kB inactivating their regulatory functions on target genes. In the case of normal human T lymphocytes, IL-2 transcription is markedly reduced. Since the publication of our work several groups have found pparg agonist drugs to have efficacy in treating autoimmune disorders. We subsequently have identified additional endogenous ligands for pparg that are produced by IL-4 stimlulated monocytes suggesting that pparg agonists may find a place in clinical immunoregulation. (2) We have examined the role of the inflammatory cytokine IL-6 on the LnCap prostate cell line. We found that IL-6 activates the androgen receptor (AR), in a steroid-independent (androgen) manner. This supports the hypothesis that inflammatory cytokines may facilitate the promotion of prostate cancer in a steroid independent manner. The mechanism of IL-6 activation of the androgen receptor was via the formation of a transcriptional complex between STAT3 and AR, thus activating the transcriptional activity of AR with AR dependent genes. (3) Almost all human Multiple Myeloma (MM) cells have been shown to express estrogen receptors. We have examined the effects of estrogens (ES) on MM cell growth. ES and Tamoxifen were found to induce MM cell apoptosis in all cell lines tested. ES apparently induces a gene/protein called PIAS3 which specifically complexes with the IL-6 stimulated or constitutively activated STAT3 transcription factor, blocking its activity. Blocking STAT3, either by dominant-neg STAT3 constructs, or by nuclear receptor (ER) cross talk mechanisms, induces apoptosis in MM cell lines. (4) We have recently identified a """"""""new"""""""" non-STAT mediated signal mechanisms for a/b and gamma interferons. Interferons, primarily are believed to function through the activation of STAT transcription factors. We have shown that a major component of the a/b interferon signal transcription complex, p48, must first be upregulated transcriptionally itself. We extensively analyzed the promoter of p48 and found that the transcription factor CEBP-b is required. Thus, a/b interferon activated CEBP-b, not STATs, in order to control the transcription of p48. This is the first non-STAT pathway to be identified with human a/b signal transduction.
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