Inhibition of human erythroid colony-forming units by interferons alpha and 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 erythropoiesis in vitro. By utilizing a cell population enriched for human erythroid colony-forming units (CFU-E), we have previously demonstrated that the inhibitory effects of beta- and gamma-IFNs are direct effects, not requiring the presence of accessory cells, and that the inhibitory effect of recombinant human (rh) gamma-IFN could be corrected by high concentrations of rh erythropoietin (Epo). In this study, we compared 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 rh(alpha)-IFN is indirect and is mediated by a soluble factor released from T lymphocytes in response to rh(alpha)-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 effects of neither alpha- nor beta-IFN could be overcome by high levels of rhEpo. These findings imply that alpha- and beta-IFN exert different cellular effects despite binding to the same receptor. Failure of rhEpo 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 response to different doses of rhEpo in patients with the anemia of chronic disease.
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Hematology/Oncology Division, University of Cincinnati College of Medicine, OH 45220, USA.
Krantz
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SB
D000740:Anemia / Q000503:physiopathology; D001773:Blood Cells / Q000166:cytology; D001854:Bone Marrow Cells; D003114:Colony-Forming Units Assay; D003864:Depression, Chemical; D015672:Erythroid Precursor Cells / Q000187:drug effects*; D004921:Erythropoietin / Q000494:pharmacology; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D016899:Interferon-beta / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology; D008222:Lymphokines / Q000502:physiology*; D017471:Receptors, Interferon / Q000187:drug effects* / Q000502:physiology; D011994:Recombinant Proteins; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*
D007370:Interferon Type I; D008222:Lymphokines; D017471:Receptors, Interferon; D011994:Recombinant Proteins; D004921:Erythropoietin; D016899:Interferon-beta; D007371:Interferon-gamma