SPECIFIC VERSUS COOPERATIVE REGULATORY MECHANISMS OF THE CYTOKINE GENES THAT ARE CLUSTERED ON THE SAME CHROMOSOME

The genes for IL-3, IL-4, IL-5, IL-9, IL-13, and granulocyte-macrophag e colony-stimulating factor (GM-CSF) are known to be clustered on huma n chromosome 5q and on mouse chromosome 11. IL-2 and interferon gamma (IFN-gamma) genes are located on separate chromosome. It is well known that upon stimulation by antigen presentation, T-H1 and T-H2 subsets of T helper cells start to transcribe distinct sets of cytokine genes. Thus mechanisms should exist that transmit extracellular signals into the nucleus, thereby coordinately turning on transcriptional machiner y in cell type-specific manners. Several different mechanism exist in which specific as well as coordinated expression of cytokines are regu lated at the transcriptional level. These include (1) regulation by pr oximal cis-elements, to which specific transcription factors bind (2) regulation by distal cis-elements, such as enhancers or locus controll ing elements, especially those located several kilobases away from the target gene, and (3) enhancement of transcription by viral trans-acti vators in a pathologic state. In this article, we review the recent st udies on the above issues, with particular emphasis on our own results that support the presence of different modes of control mechanisms. W e also discuss the possible approaches to the thorough understanding o f the coordinated and specific regulation of cytokines.