TUMOR-NECROSIS-FACTOR-ALPHA IS A POTENT SYNERGISTIC FACTOR FOR THE PROLIFERATION OF PRIMITIVE HUMAN HEMATOPOIETIC PROGENITOR CELLS AND INDUCES RESISTANCE TO TRANSFORMING GROWTH-FACTOR-BETA BUT NOT TO INTERFERON-GAMMA

Since tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and t ransforming growth factor (TGF)-beta have all been shown to be specifi c inhibitors of early human hematopoiesis, we wanted to investigate th e interactions of these three cytokines on very primitive human adult bone marrow CD34(++)CD38(-) hematopoietic progenitor cells, using a pr e-colony-forming cell (pre-CFC) assay, which detects the effects of th ese cytokines on the initial phases of the differentiation of these pr imitive progenitors, which are unresponsive to interleukin (IL) 3 alon e. Surprisingly, TNF-alpha was a very potent stimulator of the prolife ration of CD34(++)CD38(-) cells and was the most potent synergistic fa ctor for the IL-3-induced proliferation of these cells of all cytokine s tested (IL-1, IL-6, granulocyte colony-stimulating factor, kit ligan d). TNF-alpha was the only cytokine that, as a single added factor, in duced substantial proliferation in CD34(++)CD38(-) cells in the presen ce of IL-3, except for kit ligand, which induced very limited prolifer ation. TNF-alpha, moreover, induced a high degree of resistance to the inhibitory effects of TGF-beta in a dose-dependent way. The inhibitor y effects of IFN-gamma, however, were not affected by the presence of TNF-alpha. We hypothesize that in situations of hematopoietic stress, TNF-alpha may abrogate the inhibitory effect of ambient TGF-beta in th e bone marrow microenvironment to allow primitive stem cells to prolif erate and differentiate in response to an increased demand for mature blood cells.