Tumor Necrosis Factor alpha (TNF-a) plays a central role in inflammation and autoimmune disease. Regulation of TNF-a biosynthesis is primarily post-transcriptional and mediated through the AU-rich element (AURE) in the 3' untranslated region (3'UTR) of its mRNA. In macrophages, AURE-dependent post-transcriptional regulation is conferred by the binding of the AURE by tristetraprolin (TTP). In contrast, both knockout and over-expression approaches indicate that TTP has no effect on TNF-a gene expression in T lymphocytes. Thus, we know precious little about AURE-dependent regulation of TNF-a in T lymphocytes. Recent studies suggest that AURE-dependent, cytokine mRNA degradation occurs in the proteasome. Thus, rapid mRNA turnover of TNF-a in an AURE-dependent manner may depend on transport to the proteasome. Recent studies in our laboratory have supported this model: TTP mutants that contain disabling mutations in their proteasomal targeting sequences lack biologic activity. We propose to carefully examine the post-transcriptional regulation of TNF-a in the T lymphocyte. Since TNF-a biosynthesis by T cells is regulated at a post-transcriptional level that is orders of magnitude more important than transcription, these studies will define a critical regulatory pathway in inflammation and immunity. In addition, the unique nature of TNF-a AURE-dependent gene expression in T lymphocytes suggests the presence of tissue-specific regulatory pathways. If these pathways are identified and characterized, this would open the door for targeted modulation of cytokine biosynthesis by the adaptive immune response that would have considerable importance in the treatment of inflammation, autoimmune diseases, and cancer.
Showing the most recent 10 out of 129 publications
