Cytokine networks involved in the regulation of haemopoietic stem cell proliferation and differentiation.

Additive and synergistic interactions between haemopoietic growth factors and cytokines can be demonstrated in vitro in clonogenic and suspension cultures of murine and human bone marrow. Purification of early stem cells by combinations of purging with cytotoxic agents (5-fluorouracil, 4-hydroperoxy-cyclophosphamide) and selection with monoclonal antibodies for CD34+, CD33- cells permits analysis of factor interactions at the level of the primitive pluripotential stem cell. Interactions between interleukins, tumour necrosis factor and the colony-stimulating factors can be monitored. In vivo, IL-1 alone, or in combination with G-CSF produces accelerated reconstitution of haemopoiesis after chemotherapy, irradiation and bone marrow transplantation in murine and primate systems. IL-1 elicits cytokine cascades that may have positive or negative actions on lymphohaemopoiesis. Induction of products of the cyclooxygenase and lipooxygenase pathways, as well as tumour necrosis factor and TGF-beta, modulate haemopoiesis.