INHIBITION OF HUMAN ERYTHROID COLONY-FORMING-UNITS BY INTERFERON-ALPHA AND INTERFERON-BETA - DIFFERING MECHANISMS DESPITE SHARED RECEPTOR

Previous investigations have demonstrated that interferons alpha, beta , and gamma (alpha-, beta-, and gamma-IFN) are potent inhibitors of er ythropoiesis in vitro. By utilizing a cell population enriched for hum an erythroid colony-forming units (CFU-E), we have previously demonstr ated that the inhibitory effects of beta- and beta-IFNs are direct eff ects, not requiring the presence of accessory cells, and that the inhi bitory effect of recombinant human (rh) gamma-IFN could be corrected b y high concentrations of rh erythropoietin (Epo). In this study, we co mpared the effects of rh alpha-IFN on cells enriched for CFU-E to its effects on unpurified marrow cells and found that although h beta-IFN (which shares a common receptor with alpha-IFN) directly inhibits CFU- E colony formation, the effect of rha-IFN is indirect and is mediated by a soluble factor released from T lymphocytes in response to rh alph a-IFN. However, rh alpha-IFN enhanced the direct inhibitory effect of rh gamma-IFN on CFU-E not inhibited by rh alpha-IFN. The inhibitory ef fects of neither alpha- nor beta-IFN could be overcome by high levels of rhEpo. These findings imply that alpha- and beta-IFN exert differen t cellular effects despite binding to the same receptor. Failure of rh Epo to correct CFU-E colony inhibition by alpha- and beta-IFNs but not by gamma-IFN also suggests a mechanism for the differing degrees of r esponse to different doses of rhEpo in patients with the anemia of chr onic disease.