Interferon‐γ exerts its negative regulatory effect primarily on the earliest stages of murine erythroid progenitor cell development

Abstract

Interferon-gamma (INF-gamma) has been shown to suppress erythropoiesis and perhaps to contribute to the anemia of chronic disease. In this study we demonstrated that the concentration of INF gamma required to suppress murine burst forming unit-erythroid (BFU-E) growth was significantly less than that required to suppress colony forming unit-erythroid (CFU-E) growth. INF gamma acted at the most primitive step in erythroid progenitor cell differentiation and proliferation, as inhibition was maximal when added at the time of BFU-E culture initiation. Inhibition was progressively less if INF gamma addition was delayed after culture initiation. The effects of INF gamma on BFU-E did not require the 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 antibodies against IL-1 alpha, TNF alpha, or GM-CSF. This applied whether INF gamma was added to culture with individual antibodies or with a combination of all three antibodies. INF gamma was not required for IL-1 alpha- or TNF alpha-induced suppression of BFU-E, as their effects were not neutralized by a monoclonal anti-INF gamma antibody. In contrast, GM-CSF-induced suppression of BFU-E was negated by the simultaneous addition of anti-INF gamma. We have previously shown that the addition of TNF alpha does not suppress BFU-E growth in cultures from marrow depleted of macrophages. Suppression did occur, however, if a small concentration of INF gamma that does not inhibit and increasing concentration of TNF alpha were added to culture, suggesting a synergistic effect between INF-gamma and TNF alpha. These observations suggest that INF gamma is a potent direct inhibitor of erythroid colony growth in vitro. It exerts its negative regulatory effect primarily on the earliest stages of erythroid progenitor cell differentiation and proliferation, as much higher doses are required to suppress late erythroid cell development. INF gamma is also involved in GM-CSF-induced inhibition of BFU-E colony growth.

Anemia of chronic disease and defective erythropoietin production in patients with celiac disease

“…Interleukin-6 plays a major role in systemic juvenile chronic arthritis 32 and in many cases of ACD through its effects on iron homeostasis 22 and has been suggested to increase erythropoietin production. 33 In contrast, interferon-γ inhibits erythropoietin secretion in vitro, 34 and has suppressive effects on erythroid progenitors 9 and iron release from monocytes/macrophages. 10 In our patients serum levels of interferon-γ were inversely related to Hb concentration and were higher in ACD than in iron-deficiency anemia.…”

“…In fact, systemic inflammation as evidenced by increased serum levels of acute phase proteins is uncommon in celiac disease, although gliadin-dependent activation of mucosal lamina propria mononuclear cells causes overproduction of pro-inflammatory cytokines such as interferon-γ and interleukin-6, 6-8 both mediators of ACD. 9,10 In the present study we investigated the pathogenesis of anemia in patients with celiac disease.…”

STAT6-mediated suppression of erythropoiesis in an experimental model of malarial anemia

“…47 The difference in IFN-γ mRNA levels between infected WT and IL-4 -/-mice was found to be even more dramatic in CD4 + T cells enriched from the spleen. Although IFN-γ has been demonstrated to suppress erythropoiesis in vitro and in vivo in animal models as well as in humans, 30,31,48,49 its role in suppressing erythropoiesis during malaria infection has been difficult to demonstrate due to the critical role of this cytokine in innate and adaptive immune responses. 27 Our data suggest a possible role for IFN-γ in STAT6-induced erythropoietic suppression during P. chabaudi infection and are consistent with recent data in IFN-γ --/-mice infected with P. yoelii.…”

Clinical, Hematologic, and Immunophenotypic Characterization of Canine Large Granular Lymphocytosis

“…An inhibitory effect on erythropoiesis by human LGLs has been demonstrated in vitro, 17 most likely due to LGL-produced ␥-interferon, which is a potent inhibitor of murine erythroid colony growth. 46 The neutropenia in some human patients has been corrected by granulocyte-macrophage colony-stimulating factor administration. 16 The eight dogs in group 3 also had persistent LGL lymphocytosis but were not anemic at initial diagnosis.…”