DIRECT SYNERGISTIC EFFECTS OF LEUKEMIA INHIBITORY FACTOR ON HEMATOPOIETIC PROGENITOR-CELL GROWTH - COMPARISON WITH OTHER HEMATOPOIETINS THAT USE THE GP130 RECEPTOR SUBUNIT

Because leukemia inhibitory factor (LIF) has little or no effect on mu rine hematopoietic progenitor cell growth yet enhances hematopoiesis i n vivo, we sought to determine whether the effects of LIF were directl y or indirectly mediated, or a combination of both. Although LIF alone or in combination with granulocyte-macrophage colony-stimulating fact or (GM-CSF) or interleukin-3 (IL-3) has no effect on colony formation of unfractionated bone marrow cells (BMCs), it enhances M-CSF-induced colony formation. In comparison, LIF synergizes with IL-3, GM-CSF, M-C SF, and Steel Factor (SLF) to promote the colony formation of partiall y purified lineage-negative (Lin(-)) BM progenitors without altering t heir differentiation. These effects were directly mediated since ident ical results were observed in single-cell assays. Comparing the effect of LIF with other members of this subclass of hematopoietins (IL-6, o ncostatin M [OSM], and ciliary neurotrophic factor [CNTF]), we found t hat while LIF and IL-6 equally synergize with M-CSF and SLF to promote the colony formation of Lin(-) BMCs, OSM, and CNTF have no effect. In agreement with OSMs ability to directly bind gp130, preincubation of BMCs with OSM inhibits progenitor cell growth stimulated by the combin ation of LIF or IL-6 plus SLF. LIF can also directly enhance the growt h of further purified more primitive Lin(-) c-kit(+) progenitor cells in the presence of IL-3, GM-CSF, or SLF. Thus, LIF can directly synerg ize with growth factors to promote the proliferation of purified hemat opoietic progenitors, suggesting that the direct effects of LIF on hem atopoietic cell growth can, in part, explain the observed hematopoieti c effects in vivo.