THE COLONY-STIMULATING FACTORS INDUCE EXPRESSION OF INSULIN-LIKE GROWTH-FACTOR-I MESSENGER-RIBONUCLEIC-ACID DURING HEMATOPOIESIS

Murine bone marrow cells cultured in the presence of colony-stimulatin g factor-1 (CSF-1) showed coordinate induction of insulin-like growth factor-I (IGF-I) messenger RNA (mRNA) during the differentiation proce ss, and these transcripts increased approximately 50- to 75-fold over the virtually negligible levels measured in freshly isolated bone marr ow. In contrast, transcripts for the IGF-I receptor were evident in fr eshly isolated rat bone marrow cells and showed a 50% down-regulation during differentiation. Addition of a variety of single lineage and mu ltilineage CSFs, including CSF-1, interleukin-3, granulocyte-maerophag e-CSF, and granulocyte-CSF to mouse bone marrow cultures revealed that induction of IGF-I mRNA is a universal feature of differentiation wit h these CSFs, although IGF-I transcripts are at least 10- to 20-fold h igher in CSF-1- and interleukin-3-differentiated lineages than in othe r cultures. The IGF-I induced CSF-1 was biologically active because a natural ligand of IGF-I, IGF-binding protein-3, caused significant dow n-regulation of cellular proliferation, and this could be reversed by the addition of exogenous IGF-I. In addition, whereas IGF-I mRNA could be detected in resident peritoneal macrophages, these transcripts wer e increased 6-fold after a local injection of thioglycollate, a stimul us that induces macrophage proliferation and differentiation in vivo. These results show that CSFs induce expression of the growth factor IG F-I during differentiation of hematopoietic cells into multiple myeloi d lineages and that this endogenously produced IGF-I is also a growth factor for hematopoietic cells. The induction of IGF-I mRNA during hem atopoiesis should provide a new approach to understanding the expressi on of this gene during development and differentiation.