Lipoxins (FA0304)

From LipidomicsWiki

Jump to: navigation, search

Lipoxins (LXs), an anocrym for lipoxygenase interaction products, are specific lipid mediators, formed during cell-cell interaction and play an important role in anti-inflammation and as a signal for a resolution phase of acute inflammatory responses in human and mammalian systems (McMahon et al., 2001). Three enzymes are required for formation of leukotrienes: 5-lipoxygenase (5-LO), LTC4 synthase and LTA4 epoxide hydrolase and there are three major pathways leading to biosythesis of lipoxins. The first pathway involves platelet-leukocyte interaction and starts with the insertion of molecular oxygen at the C5 position in arachidonic acid (Fig.18).

Figure 23: Leukocyte-platelet interaction and lipoxin biosynthesis (Serhan, 2005)
Figure 23: Leukocyte-platelet interaction and lipoxin biosynthesis (Serhan, 2005)

The production of leukotriene LTA4 involves 5-LO in neutrophils and is followed by the abstraction of hydrogen from C13 and insertion of oxygen at C15, is released from neutrophils as LTA4 and converted to LXA4 and LXB4 by 12-LO in platelets upon their adherence. The bioactive LXA4 and LXB4 are end products of these reactions. Platelets don’t produce lipoxins on their own, but become the major source of lipoxins when they adhere to PMN (Chiang et al. 2005).

In the second type of LX generation oxygenation of arachidonic acid at the C15 position in the presence of 15-LO generates 15S-hydroperoxyeicosatetraenoic acid (15S-HpETE) or the reduced alcohol form 15S-hydroxyeicosatetraenoic acid (15S-HETE), which serve as substrates for 5-LO. The product of this reaction is 5S-hydroxyperoxy, 15S-hydro(peroxy)-DiH(p)ETE, which is rapidly converted to 5(6)-epoxytetraene. Once formed, 5(6)-epoxytetraene is subject to hydrolase activity to generate lipoxin A4 or lipoxin B4. 5-lipoxygenase, the first enzyme of this biosythesis, is highly expressed in neutrophils and monocytes and is upregulated upon stimulation with IL-4 and IL-13 (Serhan et al. 1997). 5-lipoxygenase has been found in cytosol and in the nucleus. Upon activation the enzyme translocates to the perinuclear membrane, where it becomes catalytically active (Peters-Golden et al. 1993). The 5-LO action is regulated at the level of gene transcription, translation and enzyme translocation but also availability of free arachidonic acid as an important factor stimulating 5-LO activity.

Esterification of 15-HETE in phospholipids, especially inositol-containing phospholipds, within the membrane of neutrophiles can play important source of lipoxins in tissues during inflammation (Serhan, 2005). Cells rapidly take up and esterify 15-HETE into their inositol-containing lipids, which upon agonist stimulation is released and converted into LXs. This suggests that precursors of lipoxins may be stored within the membranes and released upon inflammatory conditions (Brezinski et al. 1990). The third pathway to generate lipoxins is triggered by aspirin. Aspirin, in inflammatory state, acetylates COX-2 and shifts its activity from endothelial cell prostanoid production towards 15-HETE generation. COX-2 –derived HETE can be converted by 5-LO to carbon-15 position R epimers, known as 15-epi-LX or aspirin-triggered lipoxin (ATL) (Claria et al. 1995).

The anti-inflammatory effects of LXA4 are mediated via ALX receptor belonging to the G protein-coupled receptors superfamily. ALX has been identified in various cell types, including PMN, monocytes, activated T cells and enterocytes (Chiang et al. 2005). However, ALX is not a specific receptor for LXA4 as it has been shown to interact with other small lipids and to transmit different signals. Both lipoxins and ATL are rapidly inactivated by local metabolism, via dehydrogenation and ω oxidation mediated by prostaglandin dehydrogenase in monocytes (Kieran et al. 2004).

Personal tools
Create a book