Placenta growth factor induces 5-lipoxygenase-activating protein to increase leukotriene formation in sickle cell disease

Abstract

Individuals with sickle cell disease (SCD) have increased inflammation, a high incidence of airway hyperreactivity (AH), and increased circulating leukotrienes (LT). We show that expression of 5-lipoxygenase and 5-lipoxygenase activating protein (FLAP), key catalytic molecules in the LT pathway, were significantly increased in peripheral blood mononuclear cells (MNCs) in patients with SCD, compared with healthy controls. Placenta growth factor (PlGF), elaborated from erythroid cells, activated MNC and THP-1 monocytic cells to induce LT production. PlGF-mediated increased FLAP mRNA expression occurred via activation of phosphoinositide-3 (PI-3) kinase, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and hypoxia inducible factor-1-α(HIF-1α). HIF-1αsmall interfering RNA (siRNA) reduced PlGF-induced FLAP expression. FLAP promoter-driven luciferase constructs demonstrated that PlGFmediated luciferase induction was abrogated upon mutation of HIF-1αresponse element (HRE), but not the nuclear factor- -KB (NF-K;B) site in the FLAP promoter; a finding confirmed by chromatin immunoprecipitation (ChIP) analysis. PlGF also increased HIF-1αbinding to the HRE in the FLAP promoter. Therefore, it is likely that the intrinsically elevated levels of PlGF in SCD subjects contribute to increased LT, which in turn, mediate both inflammation and AH. Herein, we identify a mechanism of increased LT in SCD and show HIF-1αas a hypoxia-independent target of PlGF. These studies provide new avenues to ameliorate these complications. ©2009 by The American Society of Hematology.