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193 PLACENTAL GROWTH FACTOR PROTECTS ERYTHROID CELLS FROM CYTOKINE-MEDIATED APOPTOSIS.
  1. G. Dallalio,
  2. E. Law,
  3. R. T. Means Jr
  1. VA Medical Center and the University of Kentucky/Markey Cancer Center, Lexington, KY

Abstract

Inflammatory cytokines suppress erythropoiesis as part of the pathogenesis of anemia of chronic disease. 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 and that its circulating concentration is 50% higher in patients with severe sickle cell disease than it is in healthy controls (Blood 2003;102:1506-13 and 1514-24). 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 subsequent studies, we observed that CFU-E from SS patients were less sensitive to inhibition by recombinant human gamma interferon (rhIFN) than those from healthy controls, with this effect being most pronounced at lower IFN concentrations. The potential contribution of PlGF to this process was then evaluated. At PlGF concentrations 10-1,000 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 rhIFN on CFU-E colony formation (p = .04). This effect was most apparent at lower rhgIFN concentrations and was investigated using the HCD57 cell line. PlGF decreased apoptosis induced by rh IFN. This effect was associated with a significant attenuation by PlGF of rhIFN induction of Fas ligand. HCD57 cells were shown to express Flt-1, a receptor for PlGF. 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.

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