Molecular and cellular biology of interleukin-3.

The cloning and expression of the genes for rat, mouse, and human IL-3 have resulted in major advances in our knowledge of this lymphokine and the biological processes in which it is involved. Such advances include the primary structures of the IL-3 proteins, the nucleotide sequences of the IL-3 genes, and the elucidation of the retroviral insertion that resulted in constitutive synthesis of IL-3 by the leukemic cell line WEHI-3B. These advances have facilitated studies of the control of IL-3 gene expression in normal and malignant cells, which is an ongoing area of interest. The use of the cloned IL-3 gene in a retroviral expression vector has allowed the generation of experimental autocrine leukemias from IL-3-dependent cell lines. The use of recombinant rat, mouse, and human IL-3 has verified that IL-3 is a multilineage hemopoietic regulator in each of these species. Although it is clear that in each of the above species IL-3 promotes the growth of a wide variety of myeloid progenitors, the regulation of stem-cell division and maturation by IL-3 and its synergism with other regulators requires clarification and remains an active area of research. The discovery that hemopoietic stem cells from certain murine strains do not proliferate in response to IL-3 alone has provided a model system in which to analyze the synergistic activities of IL-3. It will be interesting to see whether analogous differences in the responsiveness of stem cells to IL-3 also exist in humans. Our work on the ontogeny of blood cell development in embryonic and fetal mice indicates that in every strain, early hemopoietic progenitor cells respond to IL-3 plus M-CSF, or to IL-3 plus IL-4, rather than to IL-3, M-CSF, or IL-4 alone. The difficulties encountered in acquiring sufficient cells to work with from embryonic sources could possibly be overcome by developing a fetal sheep model in which access to the embryo and fetus can be achieved at several sequential points in development. It may then be possible to determine the molecular events that regulate primitive stem-cell responsiveness to IL-3 as well as other hemopoietic cytokines. Recombinant IL-3 proteins should continue to prove valuable in further biological studies of IL-3, in the generation of monoclonal antibodies against IL-3, and for further studies of the IL-3 receptor.(ABSTRACT TRUNCATED AT 400 WORDS)