Induction of interleukin-6 (IL-6) gene expression is mediated by numerous agents involving all major signal transduction pathways. We have compared the effects of prostaglandins and their second messenger cyclic AMP (cAMP) with the effect of lipopolysaccharide (LPS) on IL-6 gene expression. We demonstrate that secretion of IL-6 is induced by cAMP in marine monocytic PU5-1.8 cells, even though to a lesser extent than by LPS. Nevertheless, cAMP and prostaglandins of the E series in the presence of theophylline induce transcription of the IL-6 promoter more strongly than LPS, suggesting distinctive effects of cAMP and LPS on posttranscriptional events. Mutations within four regulatory elements, namely, the multiple response element (MRE), AP-l, NF-IL6, and NF-KB sites, significantly reduce, but do not completely abrogate, inducibility by cAMP and prostaglandin El, whereas alterations of four additional sites have no effects. LPS-induced promoter activity, however, is almost completely abolished by mutations in the NF-KB site, suggesting that a single regulatory element is crucial for inducibility by LPS. Stimulation by cAMP is correlated with the binding of inducible factors to the AP-l, NF-IL6, and NF-KB elements, whereas factors binding to the MRE are constitutively expressed. Recombinant cAMP response element-binding protein binds to the MRE, indicating a potential role for this factor in the cAMP response. Our results suggest that cAMP and prostaglandins act through multiple, partially redundant regulatory elements to induce IL-6 expression in monocytic cells. Nuclear events that overlap partially with the LPS response but also exhibit distinctive features are involved.

The ets gene family encodes a group of proteins which function as transcription factors under physiological conditions and, if aberrantly expressed, can cause cellular transformation. We have recently identified two regulatory elements in the murine immunoglobulin heavy-chain (IgH) enhancer, TT and ,uB, (for a review, see reference 46). Interestingly, each of these regulatory regions contains several, at least partially redundant B-cell-specific enhancer elements, none of them being completely essential for the regulation of the IgH gene (42,49,58

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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.

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