Suppression of normal human erythropoiesis by gamma interferon in vitro. Role of monocytes and T lymphocytes.

Abstract

Interferons (IFN) have been shown to suppress the proliferation of human erythroid progenitors (erythroid burst-forming units IBFU-EI and colony-forming units [CFU-E]) in vitro. To examine the mechanism(s) underlying this inhibitory activity, the effect of different doses (50-10,000 U) of a highly purified preparation of recombinant DNA producfd human 'y-IFN on erythroid colony formation by normal human bone marrow BFU-E and CFU-E in the presence and absence of monocytes and/or T lymphocytes was studied. The addition of y-IFN to whole marrow caused suppression of BFU-E (6-65%) and CFU-E (31-79%) in a dose-dependent fashion. This inhibition occurred both with the direct addition of y-IFN to the culture plates as well as by the preincubation of marrow cells with y-IFN followed by the washing of the cells; at the highest concentration of y-IFN (10,000 U), near-maximal inhibition of colony formation occurred with as little as 15 min of preexposure (BFU-E, 50%; CFU-E, 81%). Removal of monocytes and/or T lymphocytes before the addition of "y-IFN significantly reduced the inhibitory effects of this lymphokine (BFU-E, -1 to 38%; CFU-E, -8 to 67%). Co-culture of purified autologous monocytes or T cells preexposed to 'y-IFN with monocyte and T cell-depleted marrow cells resulted in highly significant inhibition of erythroid colony formation even when these treated cells comprised <1% of the total nucleated cell populations in culture. The inhibitory action of y-IFN was not prevented or reversed by erythropoietin. These results demonstrate that the inhibitory effects of -y-IFN on erythropoiesis are mediated to a significant degree through accessory cell populations, and suggest that 'y-IFN may represent a useful tool in the study of the role of immunocompetent cells in the regulation of erythropoiesis in vitro.

A novel role for STAT1 in regulating murine erythropoiesis: deletion of STAT1 results in overall reduction of erythroid progenitors and alters their distribution

“…[27][28][29][30][31][32] We have analyzed the effect of IFN-␣ and IFN-␥ on BFU-E and CFU-E formation in wild-type and STAT1-deficient mice. IFN-␣ inhibits BFU-E and CFU-E proliferation in an identical fashion in cells isolated from wild-type and STAT1 Ϫ/Ϫ bone marrow and spleen.…”

“…[27][28][29][30][31][32] Clonogenic assays were performed to determined whether the inhibitory effects mediated by type I and type II interferons are STAT1-dependent ( Figure 3). Dose-inhibition experiments were performed with increasing concentrations of each IFN at a fixed concentration of 1 U/mL EPO.…”

Temporal Effects of Gamma Interferon Deficiency on the Course of Friend Retrovirus Infection in Mice

“…This variability could have been due to individual differences in the ability of the mice to compensate for the lack of IFN-␥. Another possibility is that IFN-␥ indirectly affected FV infection by influences on the generation of erythroid progenitors, the primary targets for FV replication (36)(37)(38). However, we did not observe any significant differences in the percentages of erythroid burst-forming units when we analyzed multiple tissues from wild-type and IFN-␥-deficient mice during acute and long-term infections (data not shown).…”

IFN-γ-mediated hematopoietic cell destruction in murine models of immune-mediated bone marrow failure

“…8,9 However, the precise roll of IFN-g in animal models, and particularly in human diseases, has not always been easy to define because of conflicting data among experiments and sometimes strikingly poor correlation between murine experiments and the clinic. [10][11][12] Effects of IFN-g on hematopoiesis, mainly assessed by progenitor assays in vitro, have been reported as both stimulatory [13][14][15][16][17] and suppressive [18][19][20][21][22][23] under various circumstances. IFN-g has been reported to stimulate myelopoiesis under specific infectious conditions.…”