The role of nuclear 5-Lipoxygenase and leukotrienes on macrophage inflammatory genes regulation

• Grant number: 14/13127-1
• Support Opportunities: Scholarships abroad - Research
• Start date: September 13, 2014
• End date: December 12, 2014
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Carlos Arterio Sorgi
• Grantee: Carlos Arterio Sorgi
• Host Investigator: Robert C. Murphy
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Institution abroad: University of Colorado, Denver (CU), United States

Abstract

Inflammation is necessary for life and mostly beneficial, but sometimes inflammatory reactions can become excessive, and lead to harmful outcome. In several endemic diseases chronic inflammation is part of the pathophysiology. 5-Lipoxygenase (5-LO) has a central role in the biosynthesis of leukotrienes (LTs) an important inflammatory mediators. LTs responses, which are often thought to have a quick onset and short duration, are mediated through G-protein coupled receptors such as BLT1/2 for LTB4 and CysLT1/2 for the cys-LTs. Not only is 5-LO involved in LTs biosynthesis, but its catalytic product, 5(S)-hydroperoxy-6-trans-8,11,14-cis-eicosatetraenoic acid (5-HPETE) can also be further metabolized to 5-HETE, 5-oxo-ETE and the Lipoxin (LXs) family of lipid mediators. LTs can also affect gene expression, leading to longer lasting effects. Various findings (from mouse gene modifications and gene polymorphisms) have also indicated that 5-LO gene and LTs have a role in atherosclerosis, rheumatoid arthritis, inflammation of infarcted myocardium, and the hyper-reactive chronically inflamed lung tissue of the asthma patient, and others chronic inflammatory disease, as thereby increasing the interest in this pathway. In addition, possible functions of 5-LO metabolites in the growth and survival of cancer cells have emerged. Also, a connection between 5-LO and bone metabolism is evident. These connections with pathophysiological processes have motivated studies on the regulation and function of 5-LO. The enzyme activity of 5-LO was first described in 1976, and there are now in the scientific literature thousands papers on this lipoxygenase. However, many issues remain to be resolved. Thus, new findings on activation of the 5-LO enzyme might lead to future novel therapeutic possibilities. An intra-nuclear localization of 5-LO confers higher enzyme activity in most cell types. So, our main question is how does this increase in activity arise, and does 5-LO per si or derived-products have another role inside the nucleus as a direct regulator of gene expression.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

SORGI, CARLOS A.; ZARINI, SIMONA; MARTIN, SARAH A.; SANCHEZ, RAPHAEL L.; SCANDIUZZI, RODRIGO F.; GIJON, MIGUEL A.; GUIJAS, CARLOS; FLAMAND, NICOLAS; MURPHY, ROBERT C.; FACCIOLI, LUCIA H.. Dormant 5-lipoxygenase in inflammatory macrophages is triggered by exogenous arachidonic acid. SCIENTIFIC REPORTS, v. 7, SEP 8 2017. (14/07125-6, 14/13127-1, 15/00658-1)