Proinflammatory phenotype with imbalance of KLF2 and RelA: Risk of childhood stroke with sickle cell anemia

Judy Enenstein, Liming Milbauer, Evidio Domingo, Alexandra Wells, Mark Roney, Jim Kiley, Peng Wei, Robert P Hebbel

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

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 NFκB/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 NFκB 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 TNFα/IL1β-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 TNFα/IL1β 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.

Original languageEnglish (US)
Pages (from-to)18-23
Number of pages6
JournalAmerican Journal of Hematology
Volume85
Issue number1
DOIs
StatePublished - Jan 2010

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