Molecular Biology of Cytokines

The development of the technological armamentarium of molecular biology has revolutionized biomedical research in general and nephrologic investigation in particular. In addition to the recent identification of several genes involved in normal kidney function and pathologic conditions, our knowledge regarding the role of cytokines in primary renal diseases, transplant rejection, and dialysis effects has expanded greatly. In particular, molecular biologic methodology has provided insight into the mechanisms controlling cytokine gene regulation, which occurs primarily at the transcriptional level and is mediated by DNA-binding proteins interacting with specific recognition motifs in genetic promoter and enhancer elements. Interleukin-6 (IL-6) is discussed as an example because it is a secretory product of mesangial cells and participates in the cytokine network that determines glomerular and interstitial inflammation. In our analysis of IL-6 gene regulation employing reporter gene and electrophoretic mobility shift assays, we have found that bacterial lipopolysaccharide and cyclic adenosine monophosphate synergistically induce IL-6 expression in macrophages through at least four transcription factors, including AP-1, cAMP-responsive element-binding protein (CREB), NF-IL6, and NF-kappa B. One of the most exciting areas of future research will focus on transcription factor activation in experimental and clinical disease states. Novel therapeutic approaches targeting transcriptional regulation are currently being explored.