Abstract
Although sickle cell anemia is the result of an abnormality in the beta globin chain of hemoglobin, its clinical manifestations cannot be explained solely on that basis. Inflammatory mechanisms contribute to the clinical syndromes associated with sickle cell disease. Placental growth factor (PlGF) is a member of the vascular endothelial growth factor family and is associated with inflammation and with pathologic angiogenesis. Perelman and colleagues have reported that PlGF is released from marrow erythroid cells (
Blood 2003;102:1506–13
). These and other investigators have reported that serum PlGF concentration distinguishes patients with sickle cell disease from healthy controls, although results vary depending upon disease activity at the time of study (Blood 2003;1514–24
and Brit J Haematol 2006;134:116–9
). In studies we reported previously, we measured PlGF and other cytokines in the marrow of stable homozygous sickle cell (SS) patients and controls. Plasma PlGF did not differ between homozygous sickle cell SS patients and controls, but bone marrow PlGF concentrations were significantly higher in SS patients. This was not a phenomenon general to cytokines, and did not reflect increased erythroid activity but rather represented an increase per erythropoietic unit (J Invest Med 2005;53:S305–6
). In this report, we address the consequences of exposure to PlGF for erythropoiesis in the context of inflammation. We observed that CFU–E from SS patients were less sensitive to inhibition by recombinant human gamma interferon (rhgIFN) than those from healthy controls, with this effect being most pronounced at lower gIFN concentrations. The potential contribution of PlGF to this process was evaluated. At PlGF concentrations 10 – 1000 pg/mL, no inhibition or enhancement of CFU-E colony formation was observed, and there were no differences between the responses of progenitors from SS patients or from normal volunteers to PlGF. However, PlGF 100 pg/mL reversed the inhibitory effects of rhgIFN on CFU-E colony formation (p = 0.04). This effect was most apparent at lower rhgIFN concentrations. Using the HCD57 erythroleukemia cell line as a model, it was found that PlGF produced significant attenuation of Fas ligand induction by rhgIFN. Both HCD57 and CD36+ human marrow mononuclear cells were shown to express Flt-1, a receptor for PlGF. Neutralizing antibody against Flt-1 attenuated the gIFN-protective effect of rhPlGF on CFU-E colony formation. In conclusion, increased PlGF concentrations in the marrow of stable SS patients may contribute to protecting erythroid progenitors from cytokine-induced apoptosis, and may be a mechanism by which erythropoiesis in sickle cell disease is preserved despite concurrent inflammation.Disclosure: No relevant conflicts of interest to declare.
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2006, The American Society of Hematology
2006
