INTERFERON-GAMMA EXERTS ITS NEGATIVE REGULATORY EFFECT PRIMARILY ON THE EARLIEST STAGES OF MURINE ERYTHROID PROGENITOR-CELL DEVELOPMENT

Interferon-gamma (INF gamma) has been shown to suppress erythropoiesis and perhaps to contribute to the anemia of chronic disease. in this s tudy we demonstrated that the concentration of INF gamma required to s uppress murine burst forming unit-erythroid (BFU-E) growth was signifi cantly less than that required to suppress colony forming unit-erythro id (CFU-E) growth. INF gamma acted at the most primitive step in eryth roid progenitor cell differentiation and proliferation, as inhibition was maximal when added at the time of BFU-E culture initiation. Inhibi tion was progressively less if INF gamma addition was delayed after cu lture initiation. The effects of INF gamma on BFU-E did not require th e presence of interleukin-1 alpha (IL-1 alpha), tumor necrosis factor- alpha (TNF alpha), or granulocyte macrophage colony stimulating factor (GM-CSF), as its effects were not neutralized by monoclonal antibodie s against IL-1 alpha, TNF alpha, or CM-CSF. This applied whether INF g amma was added to culture with individual antibodies or with a combina tion of all three antibodies. INF gamma was not required for IL-1 alph a- or TNF alpha-induced suppression of BFU-E, as their effects were no t neutralized by a monoclonal anti-INF gamma antibody. In contrast, CM -CSF-induced suppression of BFU-E was negated by the simultaneous addi tion of anti-INF gamma. We have previously shown that the addition of TNF alpha does not suppress BFU-E growth in cultures from marrow deple ted of macrophages. Suppression did occur, however, if a small concent ration of INF gamma that does not inhibit and increasing concentration s of TNF alpha were added to culture, suggesting a synergistic effect between INF gamma and TNF alpha. These observations suggest that INF g amma is a potent direct inhibitor of erythroid colony growth in vitro. It exerts its negative regulatory effect primarily on the earliest st ages of erythroid progenitor cell differentiation and proliferation, a s much higher doses are required to suppress late erythroid cell devel opment. INF gamma is also involved in CM-CSF-induced inhibition of BFU -E colony growth. (C) 1995 Wiiey-Liss, Inc.(*)