CELLULAR MECHANISM OF RESISTANCE TO ERYTHROPOIETIN

Erythropoiesis is controlled by different regulators. Interleukin 3, g ranulocyte-macrophage colony-stimulating factor and stem cell factor p lay regulatory functions in the early steps of erythropoiesis. Erythro poietin (Epo) is the main factor which acts positively on the last ste ps of the production of erythrocytes in mammals. Epo is specific for t he erythroid progenitor cells and has only little effect on other cell s. The target cells for Epo are the erythroid progenitors (BFUe and CF Ue). Epo acts on these progenitors through surface receptors specific for Epo. Epo induces the proliferation and differentiation of erythroi d progenitors leading finally to reticulocytes. During this process, c ertain conditions are required to permit this differentiation: progeni tors must be present in sufficient numbers, the bone marrow environmen t must be normal, and nutrients such as folic acid, vitamin B12 and pa rticularly iron must be available. Elemental iron is an absolute requi rement for adequate haemoglobin formation. Indeed, in a normal adult, without any stimulation, the bone marrow synthesizes 4X10(14) molecule s of haemoglobin per second, each molecule containing four atoms of ir on, which roughly corresponds to 20 mg iron. On the other hand, erythr opoiesis is negatively regulated by several cytokines. These are macro phage-derived cytokines, including tumour necrosis factor-alpha (TNF-a lpha), interleukin-1 (IL-1), interleukin-6 (IL-6) and transforming gro wth factor-beta (TGF-beta). All these factors are elevated in the infl ammatory state and are implicated in the pathogenesis of anaemia of ch ronic disease. TNF-alpha has an inhibitory effect on erythroid progeni tors either directly or mediated by interferon-beta (INF-beta). IL-1 i nhibits erythropoiesis in vivo in mice and in vitro in humans. Here ag ain inhibition is either direct or mediated by INF-beta. TGF-beta indu ces anaemia when injected into mice and inhibits colony formation by e rythroid progenitors. IL-6 injected in vivo induces anaemia but its in hibitory effect on erythropoiesis in vitro is not clear. These cytokin es impaire iron metabolism by blocking iron inside the macrophages.