Monocytes from patients with sickle cell disease (SCD) are in an activated state. However, the mechanism of activation of monocytes in SCD is not known. Our studies showed that placenta growth factor (

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Sickle cell disease (SCD) results in chronic hypoxia and secondarily increased erythropoietin concentrations. Leukocytosis and activated monocytes are also observed in SCD in absence of infection or vaso-occlusion (steady state), the reasons for which are unknown. We found that erythroid cells produced placenta growth factor (PlGF), an angiogenic growth factor belonging to the vascular endothelial growth factor (VEGF) family, and its expression was induced in bone marrow CD34 ؉ progenitor cells in the presence of erythropoietin. Furthermore, the steady state circulating PlGF levels in subjects with severe SCD (at least 3 vasoocclusive crises [VOCs] per year) were 18.5 ؎ 1.2 pg/mL (n ‫؍‬ 9) compared with 15.5 ؎ 1.2 pg/mL (n ‫؍‬ 13) in those with mild SCD (fewer than 3 VOCs per year) and 11.3 ؎ 0.7 pg/mL (n ‫؍‬ 9) in healthy controls (P < .05), suggesting a correlation between PlGF levels and SCD severity. In addition, PlGF significantly increased mRNA levels of the proinflammatory cytochemokines interleukin-1␤, interleukin-8, monocyte chemoattractant protein-1, and VEGF in peripheral blood mononuclear cells (MNCs) of healthy subjects (n ‫؍‬ 4; P < .05). Expression of these same cytochemokines was significantly increased in MNCs from subjects with SCD at steady state (n ‫؍‬ 14), compared with healthy controls. Of the leukocyte subfractions, PlGF stimulated monocyte chemotaxis (P < .05, n ‫؍‬ 3). Taken together, these data show for the first time that erythroid cells intrinsically release a factor that can directly activate monocytes to increase inflammation. The baseline inflammation seen in SCD has always been attributed to sequelae secondary to the sickling phenomenon. We show that PlGF contributes to the inflammation observed in SCD and increases the incidence of vaso-occlusive events. IntroductionSickle cell disease (SCD) is characterized by sickling of red blood cells (RBCs) due to polymerization of sickle hemoglobin upon deoxygenation, resulting in vascular occlusion. Repeated sickling and oxygenation-deoxygenation damages RBC membranes and shortens their life span, causing hemolysis and anemia. Chronic hemolytic anemia, shortened life span of RBCs, and vascular occlusions are the hallmarks of the disease. 1,2 The bone marrow responds to hypoxia and anemia with an erythropoietic response, reflected by high circulating reticulocytes. 3,4 Another salient feature of SCD is leukocytosis that occurs despite absence of acute infection or inflammation. Activated monocytes, 5-7 endothelial cells, 5,7,8 neutrophils, 9,10 and the coagulation cascade 11,12 observed in SCD at steady state have been presumed to be secondary sequelae to the sickling phenomenon. 2 While activated leukocytes 13,14 have been shown to initiate and/or promote vaso-occlusion, 15 the reasons for leukocytosis, activation of monocytes and neutrophils, and increased adhesivity of endothelium at steady state are largely unknown.Activation of endothelial cells in SCD contributes to vascular occlusions. 5,7,8,16 Vascular endothelial growth factor (V...

In patients with amyloid beta-related cerebrovascular disorders, e.g. , Alzheimer's disease, one finds increased deposition of amyloid peptide (Abeta) and increased presence of monocyte/microglia cells in the brain. However, relatively little is known of the role of Abeta in the trafficking of monocytes across the blood-brain barrier (BBB). Our studies show that interaction of Abeta(1-40) with monolayer of human brain endothelial cells results in augmented adhesion and transendothelial migration of monocytic cells (THP-1 and HL-60) and peripheral blood monocytes. The Abeta-mediated migration of monocytes was inhibited by antibody to Abeta receptor (RAGE) and platelet endothelial cell adhesion molecule (PECAM-1). Additionally, Abeta-induced transendothelial migration of monocytes were inhibited by protein kinase C inhibitor and augmented by phosphatase inhibitor. We conclude that interaction of Abeta with RAGE expressed on brain endothelial cells initiates cellular signaling leading to the transendothelial migration of monocytes. We suggest that increased diapedesis of monocytes across the BBB in response to Abeta present either in the peripheral circulation or in the brain parenchyma may play a role in the pathophysiology of Abeta-related vascular disorder.