1.Introduction:
What is 5-Lipoxygenase and why we are interested in it?
1.1 5-Lipoxygenase (5-LOX) affect the inflammatory reaction through phospholipid –arachidonic acid-leucotrienes pathway
1.1.1 Translocation of 5-LOX to the nuclear membrane is the key
The subcellular localization of5-LOis regulated, with nuclear import commonly leading to increased
leukotriene production\cite{Flamand_2008}
The C2-like domain seemstobe involvedinthe Ca2+-dependent interaction of the enzyme with membrane structures. Thus, Ca2+ stimulates 5-LO translocation to the nuclear envelope as well as association of 5-LO with membranes.\cite{Woods_1993}\cite{Rouzer_1987}preferentially the nuclear membrane, which is
rich in phosphatidylcholine (PC)\cite{Kulkarni_2002}it was found that the Ca2+-binding C2-like domain is involved in the ionophore-induced association of 5-LO with the nuclear envelope\cite{Chen_2000}
In LPS-primed cells, but not in unprimed cells, cPLA2 as well as 5-LO translocate to the nuclear envelope after stimulation with fMLP, coinciding with enhanced release of AA and LTs \cite{Surette1998Mechanisms}. Thus, redistribution of 5-LO might be one mechanism of how priming increases the capacity of LT generation.
Phosphorylation of 5LO at Ser523
by protein kinase A (PKA)prevents the migration of 5LO to the perinuclear membrane, re-
sulting in decreased synthesis of LT.\cite{Luo_2005}
1.1.2 The interaction between 5-LOX and COX2 and cPLA2
Cellular formation of these mediators(LTs) is controlled by (1) liberation of AA which is mainly catalyzed by cytosolic phospholipase(cPL)A2 and (2) regulation of 5-LO activity.\cite{Werz_2005}
the cytosolic-bound 5LO processes 15R-HETE, produced
by cytosolic COX2, resulting in the production of 15-epi-LXA4,a15-epi-LXA4without potent anti-inflammatory mediator.without H-89(PKA inhinbitor), atorvastatin and pioglitazone induced an interaction between 5LO and COX2 in the cytosolic fraction to produce 15-epi-LXA4 , whereas when H-89 was added, 5LO interacted with cPLA2 to produce LB4 on the membranous fraction.The 5LO phosphorylation determines whether 15-epi-LXA4 (anti-inflammatory) or leukotriene B4(inflammatory mediator) is produced .\cite{Ye_2008}The 15-epi-LXA4
has been shown to inhibit the production of IL-6, TNF-α, and IL-8\cite{Jozsef_2002} ; inhibit neutrophil activation (chemotaxis,
adhesion, and transmigration across the vascular endothelium)\cite{Chiang_2006}。Aspirin causes acetylation of cyclooxygenase-2 (COX2), leading to the production of (15R)-15-hydroxy-5,8,11-cis-13-trans-eicosatetraenoic acid (15R-HETE) that is converted by 5-lipoxygenase (5LO) to 15-epi-LXA4\cite{Claria_1995}