Submitted July 21, 2008
Accepted October 3, 2008
Placenta growth factor induces 5-lipoxygenase activating protein to increase leukotriene formation in sickle cell disease
Nitin Patel, Caryn S Gonsalves, Minyang Yang, Punam Malik, and Vijay K Kalra*
Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
Division of Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
* Corresponding author; email: vkalra{at}usc.edu.
Individuals with sickle cell disease (SCD) have increased inflammation, a high incidence of airway hyper-reactivity (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 (MNC) in patients with SCD, compared to 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 PI-3 kinase, NADPH-oxidase and HIF-1
. HIF-1 siRNA reduced PlGF-induced FLAP expression. FLAP promoter-driven luciferase constructs demonstrated that PlGF-mediated luciferase induction was abrogated upon mutation of HIF-1 response element (HRE), but not the NF-
B site in the FLAP promoter; a finding confirmed by ChIP analysis. PlGF also increased HIF-1 binding 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-1 as a hypoxia-independent target of PlGF. These studies provide new avenues to ameliorate these complications.
