In human peripheral blood monocytes Interleukin-4 (IL4) and IL13 significantly upregulate the levels of proteins involved in inflammatory resolution including the cytoplasmic proteins 15-lipoxygenase (ALOX15) and heat shock protein 8 (HSP8) (Chaitidis et al. 2005, Yakubenko et al. 2011).

Analogous to arachidonate 5-lipoxygenase (ALOX5) biosynthesis of leukotriene A4 (LTA4), arachidonate 15-lipoxygenase (ALOX15) can form an epoxide across C-14 and C-15 to form 14,15-LTA4 aka eoxin A4 (EXA4) (Feltenmark et al. 2008, Claesson et al. 2008).

Unlike resolvins E1 and E2, both of which are biosynthesised by neutrophils via the 5-lipoxygenase pathway, resolvin E3 (RvE3) is biosynthesised in eosinophils or resident macrophages via the 15-lipoxygenase (ALOX15) pathway. 18(R)-hydroxyeicosapentaenoic acid (18(R)-HEPE) is oxidised by ALOX15 (possibly through C13-hydrogen abstraction) into a number of dihydroxy-HEPEs including 17(R),18(R)-diHEPE (18(R)-RvE3) (Isobe et al. 2012, Isobe et al. 2013).

Unlike resolvins E1 and E2, both of which are biosynthesised by neutrophils via the 5-lipoxygenase pathway, resolvin E3 (RvE3) is biosynthesised in eosinophils or resident macrophages via the 15-lipoxygenase (ALOX15) pathway. 18(S)-hydroxyeicosapentaenoic acid (18(S)-HEPE) is oxidised by ALOX15 (possibly through C13-hydrogen abstraction) into a number of dihydroxy-HEPEs including 17(R),18(S)-diHEPE (18(S)-RvE3) (Isobe et al. 2012, Isobe et al. 2013).

At sites of injury, 15 lipoxygenase (ALOX15) can oxygenate ω-3 docosapentaenoic acid (DPAn-3) to form the 17(S) epimer 17(S)-hydroperoxy docosapentaenoic acid (17(S)-Hp-DPAn-3) in neutrophils (Dalli et al. 2013). The formations of individual hydroperoxy intermediates are supported by chemical synthesis experiments (Aursnes et al. 2014, Primdahl et al. 2017) and are the pivotal intermediates in the production of DPAn-3 derived protectins and resolvins.

The 15-eicosatetraenoic acids: 15-hydroperoxy-eicosatetraenoic acid (15-HpETE), 15-hydroxyeicosatetraenoic acid (15-HETE) and 15-oxo-eicosatetraenoic acid (15-oxoETE) are formed after the initial step of arachidonic acid oxidation by the arachidonate 15-lipoxygenases (ALOX15 and ALOX15B) (Buczynski et al. 2009, Vance & Vance 2008).

The 12-eicosatetraenoic acids: 12-hydroperoxy-eicosatetraenoic acid (12-HpETE), 12-hydroxyeicosatetraenoic acid (12-HETE) and 12-oxo-eicosatetraenoic acid (12-oxoETE) are formed after the initial step of arachidonic acid oxidation by the arachidonate 12 and 15 lipoxygenases (ALOX12, ALOX12B and ALOX15 respectively). This part of the pathway is bifurcated at the level of 12S-hydroperoxy-eicosatetraenoic acid (12S-HpETE), which can either be reduced to 12S-hydro-eicosatetraenoic acid (12S-HETE) or converted to hepoxilins (Buczynski et al. 2009, Vance & Vance 2008).

Lipoxins A4 (LXA4) and B4 (LXB4), structurally characterized from human neutrophils incubated with 15-hydroperoxy-eicosatetraenoic acid (15-HpETE), each contain three hydroxyl moieties and a conjugated tetraene. The third hydroxyl of LXA4 is positioned at C-6, and of LXB4 at C-14. The action of arachidonate 5-lipoxygenase (ALOX5), in concert with an arachidonate 12-lipoxygenase (ALOX12) or arachidonate 15-lipoxygenase (ALOX15) activity, has been shown to produce lipoxins by three distinct pathways. Neutrophil ALOX5 can produce and secrete leukotriene A4 (LTA4) that is taken up by platelets, where it is acted upon by ALOX12 to form lipoxins. Likewise, ALOX15s can generate either 15-hydroperoxy-eicosatetraenoic acid (15-HpETE) or 15-hydro-eicosatetraenoic acid (15-HETE) that can be taken up by monocytes and neutrophils, where highly expressed ALOX5 uses it to generate lipoxins. Finally, aspirin acetylated prostaglandin G/H synthase 2 (PTGS2), rendered unable to synthesize prostaglandins, can act as a 15-lipoxygenase. This leads to the formation of 15R-HETE and culminates in creation of epi-lipoxins, which have altered stereochemistry at the C-15 hydroxyl but similar biological potency (Chiang et al. 2006, Buczynski et al. 2009, Vance & Vance 2008, Stsiapanava et al. 2017).