THE NETWORK OF HEMATOPOIETIC CYTOKINES

Cell viability, multiplication, and differentiation to the various hematopoietic cell lineages are induced by a multigene cytokine family, and hematopoiesis is controlled by a network of interactions between these cytokines. This network includes positive regulators such as colony-stimulating factors and interleukins, and negative regulators such as transforming growth factor-beta and tumor necrosis factor. The functioning of the network requires an appropriate balance between positive and negative regulators, and the selective regulation of programed cell death (apoptosis) by interaction of cytokines with their receptors. The cytokine network, which has arisen during evolution, allows considerable flexibility, depending on which part of the network is activated, and the ready amplification of response to a particular stimulus. This amplification occurs by autoregulation and transregulation of genes 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 infections that may develop in the future, a network may also be necessary 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 factors. Cytokine signaling through transcription factors can thus ensure the autoregulation and transregulation of cytokine and receptor genes that occur in the network. Interactions between the cytokine network and transcription factors can also ensure production of specific cell types and stability of the differentiated state.