Reduced EPO production
Under normal physiological conditions, levels of EPO are inversely correlated with hemoglobin levels and tissue oxygenation, but in chronic inflammatory conditions the EPO response is blunted, leading to inadequate levels of EPO for the degree of anemia, and this is thought to be mediated via inflammatory cytokines such as IL-1 and TNF-alpha, though not all studies confirm this.
Reduced erythroid responsiveness
In ACD, the proliferation and differentiation of erythroid progenitor cells is reduced. Early studies showed that macrophages from patients with ACD could suppress erythroid colony formation in vitro. Subsequent studies showed this effect to be due to inhibitory effects of inflammatory cytokines, especially interferon-gamma, on growth of BFU-E and CFU-E, and that this effect could be overcome by addition of high concentrations of EPO to the culture systems. Hepcidin itself has an inhibitory effect on erythropoiesis in vitro at low EPO concentrations.
It has been demonstrated that bone marrow cultures from patients with active rheumatoid arthritis showed defective growth when compared to normal controls, and that there was an inverse correlation between colony growth and levels of TNF-alpha in the culture supernatant. Moreover, these effects were reversed both in vitro and in vivo following treatment with infliximab, an antibody against TNF-alpha.