Placenta growth factor activates monocytes and correlates with sickle cell disease severity.
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 vaso-occlusive 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-1beta, 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.
Perelman
Natalya
N
Division of Hematology-Oncology, Childrens Hospital Los Angeles, CA 90027, USA.
Selvaraj
Suresh K
SK
Batra
Sandeep
S
Luck
Lori R
LR
Erdreich-Epstein
Anat
A
Coates
Thomas D
TD
Kalra
Vijay K
VK
Malik
Punam
P
D000755:Anemia, Sickle Cell / Q000097:blood* / Q000150:complications; D018952:Antigens, CD34 / Q000276:immunology; D001853:Bone Marrow / Q000378:metabolism; D018925:Chemokines / Q000096:biosynthesis; D002633:Chemotaxis / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000096:biosynthesis; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins; D015672:Erythroid Precursor Cells / Q000378:metabolism; D004921:Erythropoietin / Q000494:pharmacology; D006801:Humans; D007962:Leukocytes / Q000166:cytology; D009000:Monocytes / Q000378:metabolism*; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000096:biosynthesis* / Q000502:physiology; D012720:Severity of Illness Index; D013223:Statistics as Topic; D014157:Transcription Factors / Q000378:metabolism; D014652:Vascular Diseases / Q000097:blood / Q000209:etiology; D000097809:Transcription Factor MTF-1
D018952:Antigens, CD34; D018925:Chemokines; D016207:Cytokines; D004247:DNA; D004268:DNA-Binding Proteins; D004921:Erythropoietin; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins; D014157:Transcription Factors; D000097809:Transcription Factor MTF-1; C000608036:PGF protein, human