Interferon-α Inhibits Erythropoietin-Induced Proliferation, but Not Differentiation, and Restricts Erythroleukemia Development

Abstract

The immature erythroid cell line J2E responds to erythropoietin (Epo) by proliferating and terminally differentiating into hemoglobin-synthesizing red blood cells. These cells produce a rapid, fatal erythroleukemia in mice characterized by hepatosplenomegaly and severe anemia. The aim of this study was to investigate the effects of murine interferons-alpha (MuIFN-alpha) on J2E cells in vitro and in vivo. Here we show that in culture MuIFN-alpha inhibited the Epo-induced proliferation of J2E cells but did not interfere with differentiation. When mice with J2E erythroleukemias were treated with MuIFNs in vivo, an extension of their life span was observed. Moreover, numerous necrotic lesions of infiltrating leukemic cells were detected in the spleens of these mice. Finally, ex vivo treatment of leukemic bone marrow cells with Epo and MuIFNs delayed mortality even further. It was concluded that MuIFNs (1) suppressed the proliferation of J2E cells in vitro but did not affect Epo-induced differentiation, and (2) inhibited the progress of erythroleukemias, especially in combination with Epo.

Type I interferon differential therapy for erythroleukemia: specificity of STAT activation

“…64 Prior findings have indicated that mixed muIFN-␣ (100-300 IU/mL) stimulation of J2E cells did not intervene with Epo-induced J2E cell differentiation. 47 However, in this study, in the absence of Epo, IFN-␣4 (100 IU/mL) was able to significantly increase the percentage of hemoglobin-positive J2E cells, while higher doses of IFN-␣1 and -␣4 (1000 IU/mL) induced 5-fold and 4-fold enhancement of differentiation, respectively. Interestingly, decreased cell proliferation has been shown to potentiate Epoinduced differentiation.…”

“…62 Previous reports in erythroid cells have shown antiproliferative effects with mixed IFN-␣, IFN-␣1, and IFN-␣4. 46,47 We report here, the antiproliferative effects of 7 type I IFNs on erythroid J2E cells. In this study, all IFN subtypes examined induced an antiproliferative response in J2E cells, with cell numbers reduced by 51.3% to 67.9%, and IFN stimulation at 100 IU/mL, which was further reduced by 66.1% to 89.4% using 1000 IU/mL.…”

“…45 Previously, J2E cells stimulated with mixed murine IFN-␣ (muIFN-␣), IFN-␣1, and IFN-␣4 differed in their antiproliferative capacity, 46 while levels of Epo-induced differentiation were maintained. 47 In this report, we investigated the differential antileukemic properties of a panel of 7 type I IFN subtypes (-␣1, -␣2, -␣4, -␣5, -␣6, -␣9, and -␤) using delivery of an expression vector encoding the IFN subtype gene. Individual IFN subtypes were studied in vitro for effect on erythroid cell proliferation, differentiation, viability, and apoptosis.…”

Dominant action of mutated erythropoietin receptors on differentiation in vitro and erythroleukemia development in vivo

“…Figure 7 shows the characteristic mortality induced by J2E cells that we have reported previously (Farr et al, 1995;Lai et al, 1995). No di erence in latent period was observed with J-D321 cells, and the cumulative mortality curve was essentially superimposable with J2E cells (Figure 7).…”

Iron deficiency or anemia of inflammation?

“…Part of this may be attributed to downregulation of the EPO receptor on erythroid cells by interferon (IFN)-γ [ 90 ]. Furthermore, a range of inflammatory mediators including TNF, IL-1, IFN-γ, and reactive intermediates inhibits the proliferation and differentiation of erythroid progenitors or induces their apoptosis [ 91 – 94 ]. These pathways ultimately culminate in an insufficient renal EPO response and hematopoietic EPO resistance further aggravating anemia in AI [ 95 ].…”