ROLE OF GLYCOPROTEIN-130 AND C-KIT SIGNALING IN PROLIFERATION AND DIFFERENTIATION OF HUMAN HEMATOPOIETIC - PROGENITOR CELLS

Glycoprotein (gp) 130, a receptor component for interleukin 6 (IL-6), can associate with a soluble IL-6 receptor (sIL-6R)-IL-6 complex. To e xamine the role of gp130 signaling in human hematopoietic progenitor-c ell proliferation and differentiation, we studied the effects of the s IL-6R-IL-6 complex in combination with other cytokines on human CD34() cells in clonal and suspension cultures. The sIL-6R-IL-6 complex, bu t not sIL-6R or IL-6 alone, in the presence of stem-cell factor (SCF) produced dramatic increases in the populations of various cell lineage s, including erythroid cells and various hematopoietic progenitors, in suspension culture. Significant numbers of colonies of (particularly) multilineage and blast cells were generated in methylcellulose cultur e supplemented with a combination of sIL-6R-IL-6 complex and SCE Addit ion of anti-gp130 monoclonal antibodies (MAbs) and anti-IL-6R MAbs to the above-mentioned cultures dose-dependently inhibited the generation of cells of various lineages and of progenitor cells in suspension cu lture and completely blocked multilineage colony production in methylc ellulose culture; an anti-erythropoietin antibody did not cause inhibi tion. These findings demonstrate that both proliferation and different iation of-hematopoietic progenitor cells can be induced through gp130 and c-Kit signaling, indicating that progenitor cells are responsive t o the sIL-6R-IL-6 complex, even though they do not express IL-6R. Toge ther with previous studies showing that detectable levels of sIL-6R, I L-6, and SCF are present in human serum, these results suggest that gp 130 signaling may play an important role in human hematopoiesis in viv o.