THE GROWTH-RESPONSE OF LIN(-)THY-1(+) HEMATOPOIETIC PROGENITORS TO CYTOKINES IS DETERMINED BY THE BALANCE BETWEEN SYNERGY OF MULTIPLE STIMULATORS AND NEGATIVE COOPERATION OF MULTIPLE INHIBITORS

The present studies investigated the balance of positive and negative growth signals in direct regulation of hematopoiesis. Interleukin-3 (I L-3) combined with Steel factor (SLF) optimally stimulated proliferati on of Lin(-)Thy-1(+) murine bone marrow progenitors in single-cell ass ays, and that proliferation was inhibited more than 90% by transformin g growth factor-beta 1 (TGF-beta 1). Colony-stimulating factor-1 (CSF- 1), granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-1, o r IL-6 as a third stimulatory growth factor was incapable of counterac ting the TGF-beta 1-mediated inhibition of IL-3-plus-SLF-stimulated gr owth, while G-CSF slightly enhanced the number of TGF-beta 1-resistant clones. As a fourth factor, only IL-1 could partially overcome the TG F-beta 1-induced growth inhibition. While the presence of a cocktail o f five additional stimulatory growth factors did not enhance the frequ ency of single Lin(-)Thy-1(+) progenitors proliferating in response to IL-3 plus SLF, the number of responding progenitors in the presence o f TGF-beta 1 was enhanced nine-fold. Furthermore, tumor necrosis facto r-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), but not macropha ge inflammatory protein-1 alpha (MIP-1 alpha), cooperated with TGF-bet a 1 to reverse the proliferative effects of multiple stimulatory cytok ines, resulting in 76% inhibition. Thus, the direct effects of single inhibitory factors on hematopoietic progenitor cell growth can be reve rsed by multiple stimulatory growth factors, and negative growth facto rs can directly cooperate to suppress progenitor cell growth stimulate d by multiple positive-acting factors.