THE NETWORK OF HEMATOPOIETIC CYTOKINES

Cell viability, multiplication, and differentiation to the various hem atopoietic cell lineages are induced by a multigene cytokine family, a nd hematopoiesis is controlled by a network of interactions between th ese cytokines. This network includes positive regulators such as colon y-stimulating factors and interleukins, and negative regulators such a s transforming growth factor-beta and tumor necrosis factor. The funct ioning of the network requires an appropriate balance between positive and negative regulators, and the selective regulation of programed ce ll death (apoptosis) by interaction of cytokines with their receptors. The cytokine network, which has arisen during evolution, allows consi derable flexibility, depending on which part of the network is activat ed, and the ready amplification of response to a particular stimulus. This amplification occurs by autoregulation and transregulation of gen es for the hematopoietic cytokines. There is also a transregulation by these cytokines of cytokine receptors. In addition to the flexibility of this network, both for response to present day infections and to i nfections that may develop in the future, a network may also be necess ary to stabilize the whole system. The existence of a network and the cytokine-receptor regulation of apoptosis has to be taken into account in the clinical use of cytokines for therapy. Cytokines that regulate hematopoiesis induce the expression of genes for transcription factor s. Cytokine signaling through transcription factors can thus ensure th e autoregulation and transregulation of cytokine and receptor genes th at occur in the network. Interactions between the cytokine network and transcription factors can also ensure production of specific cell typ es and stability of the differentiated state.