Proinflammatory phenotype with imbalance of KLF2 and RelA: risk of childhood stroke with sickle cell anemia.
Altered inflammation signaling within the cerebral vasculature may be an important risk factor for stroke in children with sickle cell anemia (SCA). This study examines how differential expression of NFkappaB/p65 (RelA), KLF2, and other transcription factors may act as switches in inflammation signaling leading to observed differences between non-SCA (NS) African Americans and African Americans with SCA who are either at risk (AR) or not at risk (NAR) of childhood stroke based on occurrence of Circle of Willis disease. Clover/Transfac analysis was used to identify overrepresented transcription factor binding motifs on genes associated with inflammation. Transcription factor binding motifs for the NFkappaB family and RFX1 were overrepresented on inflammation signaling gene set analysis. Variations in protein expression were determined by flow cytometry of blood outgrowth endothelial cells (BOECs) from NS, AR, and NAR donors and Western blots of protein extracts from both unstimulated and TNFalpha/IL1beta-stimulated BOECs. BOECs from patients with SCA had more cytoplasmic-derived RelA compared with NS BOECs. Sickle BOECs also had heightened responses to inflammatory stimuli compared with NS BOECs, as shown by increased nuclear RelA, and intracellular adhesion molecule (ICAM) response to TNFalpha/IL1beta stimulation. Multiple control points in RelA signaling were associated with risk of childhood stroke. The ratio of proinflammatory factor RelA to anti-inflammatory factor KLF2 was greater in BOECs from AR donors than NS donors. Group risk of childhood stroke with SCA was greatest among individuals who exhibited increased expression of proinflammatory transcription factors and decreased expression of transcription factors that suppress inflammation.
Enenstein
Judy
J
Vascular Biology Center and Division of Hematology-Oncology-Transplantation, Department of Medicine, University of Minnesota Medical School, 420 Delaware Street SE, Minneapolis, MN 55455, USA. enens001@umn.edu
Milbauer
Liming
L
Domingo
Evidio
E
Wells
Alexandra
A
Roney
Mark
M
Kiley
Jim
J
Wei
Peng
P
Hebbel
Robert P
RP
D000293:Adolescent; D000755:Anemia, Sickle Cell / Q000150:complications* / Q000378:metabolism*; D015153:Blotting, Western; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002941:Circle of Willis / Q000473:pathology; D042783:Endothelial Cells / Q000145:classification / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D012307:Risk Factors; D020521:Stroke / Q000209:etiology*; D051996:Transcription Factor RelA / Q000378:metabolism*; D055815:Young Adult
C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; C498143:RELA protein, human; D051996:Transcription Factor RelA