Lipoxin and resolvin biosynthesis is dependent on 5‐lipoxygenase activating protein

Lehmann, Christian; Homann, Julia; Ball, Ann Katrin; Blöcher, René; Kleinschmidt, Thea K.; Basavarajappa, Devaraj; Angioni, Carlo; Ferreiròs, Nerea; Häfner, Ann Kathrin; Rådmark, Olof; Proschak, Ewgenij; Haeggström, Jesper Z.; Geißlinger, Gerd; Parnham, Michael J.; Steinhilber, Dieter; Kahnt, Astrid S.

doi:10.1096/fj.15-275487

Cited by 71 publications

(51 citation statements)

References 45 publications

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“…The literature on 5-LO in M1 and M2 Mfs is controversial. Higher 5-LO and FLAP protein expression has been reported for M1 (23), whereas other reports showed that ALOX5 mRNA was higher in M2 compared with M1 (5, 24). CLP, the other 5-LO accessory protein that also binds to F-actin, was slightly higher in M-CSF Mfs, whereas LTA 4 hydrolase was equally expressed in both cell types.…”

Section: Expression Of Eicosanoid-forming Enzymes Is Different In Gm-mentioning

confidence: 81%

GM‐CSF– and M‐CSF–primed macrophages present similar resolving but distinct inflammatory lipid mediator signatures

et al. 2017

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M1 and M2 activated macrophages (Mfs) have different roles in inflammation. Because pathogens may first encounter resting cells, we investigated lipid mediator profiles prior to full activation. Human monocytes were differentiated with granulocyte Mf colony-stimulating factor (GM-CSF) or Mf colony-stimulating factor (M-CSF), which are known to prime toward M1 or M2 phenotypes, respectively. Lipid mediators released during resting conditions and produced in response to bacterial stimuli (LPS/N-formylmethionyl-leucyl-phenylalanine or peptidoglycan) were quantified by liquid chromatography-mass spectrometry. In resting conditions, both Mf phenotypes released primarily proresolving lipid mediators (prostaglandin E 2 metabolite, lipoxin A 4 , and 18-hydroxyeicosapentaenoic acid). A striking shift toward proinflammatory eicosanoids was observed when the same cells were exposed (30 min) to bacterial stimuli: M-CSF Mfs produced considerably more 5-lipoxygenase products, particularly leukotriene C 4 , potentially linked to M2 functions in asthma. Prostaglandins were formed by both Mf types. In the M-CSF cells, there was also an enhanced release of arachidonic acid and activation of cytosolic phospholipase A 2 . However, GM-CSF cells expressed higher levels of 5-lipoxygenase and 5-lipoxygenase-activating protein, and in ionophore incubations these cells also produced the highest levels of 5-hydroxyeicosatetraenoic acid. In summary, GM-CSF and M-CSF Mfs displayed similar proresolving lipid mediator formation in resting conditions but shifted toward different proinflammatory eicosanoids upon bacterial stimuli. This demonstrates that preference for specific eicosanoid pathways is primed by CSFs before full M1/M2 activation.-Lukic, A., Larssen, P., Fauland, A., Samuelsson, B., Wheelock, C. E., Gabrielsson, S., Radmark, O. GM-CSF-and M-CSF-primed macrophages present similar resolving but distinct inflammatory lipid mediator signatures. FASEB J. 31, 4370-4381 (2017). www.fasebj.orgMacrophages (Mfs) orchestrate the inflammatory process from early onset to the resolution phase (1, 2). A major issue in Mf biology is to characterize functional phenotypes, currently described as a heterogeneous spectrum of activated states, from M1 to M2 (3, 4). Stimulating factors, such as cytokines and pathogens, can induce specific phenotypes: originally IFN-g + LPS activation resulted in a proinflammatory M1 state, whereas IL-4 activation induced the alternatively activated M2 state. Polarized cells express distinct markers, such as transcription factors, cytokines, and surface markers; these are the main tools to define Mf phenotypes. A number of transcripts have been reported to differ between M1 and M2 Mfs, including mRNAs for enzymes involved in eicosanoid metabolism (5).Eicosanoids originate from arachidonic acid (AA), released from membrane phospholipids by phospholipases, typically cytosolic phospholipase A 2 (cPLA 2 ) (6). Free AA is further metabolized via 3 enzymatic pathways: lipoxygenase (LO), cyclooxygenase (COX), and cyto...

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Section: Expression Of Eicosanoid-forming Enzymes Is Different In Gm-mentioning

confidence: 81%

GM‐CSF– and M‐CSF–primed macrophages present similar resolving but distinct inflammatory lipid mediator signatures

et al. 2017

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“…LTC4, LTD4 and LTE4 are known collectively as the cysteinyl leukotrienes and are reported to have a role in inflammatory cell recruitment, smooth muscle contraction, vessel dilation and permeability [53] (Figure 2). 5-LO is also involved in the synthesis of another type of AA-derived metabolite called Lipoxins, such as LXA4 and LXB4 which have anti-inflammatory and pro-resolving properties [54,55]. …”

Section: 5-lipoxygenase Pathway In Cancermentioning

confidence: 99%

Cross-Talk between Cancer Cells and the Tumour Microenvironment: The Role of the 5-Lipoxygenase Pathway

Moore

Pidgeon

2017

IJMS

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5-lipoxygenase is an enzyme responsible for the synthesis of a range of bioactive lipids signalling molecules known collectively as eicosanoids. 5-lipoxygenase metabolites such as 5-hydroxyeicosatetraenoic acid (5-HETE) and a number of leukotrienes are mostly derived from arachidonic acid and have been shown to be lipid mediators of inflammation in different pathological states including cancer. Upregulated 5-lipoxygenase expression and metabolite production is found in a number of cancer types and has been shown to be associated with increased tumorigenesis. 5-lipoxygenase activity is present in a number of diverse cell types of the immune system and connective tissue. In this review, we discuss potential routes through which cancer cells may utilise the 5-lipoxygenase pathway to interact with the tumour microenvironment during the development and progression of a tumour. Furthermore, immune-derived 5-lipoxygenase signalling can drive both pro- and anti-tumour effects depending on the immune cell subtype and an overview of evidence for these opposing effects is presented.

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“…PBMC isolation was performed as previously described [26]. Subsequently, T and B cell selection were carried out using T Cell Enrichment kit as well as Dynabeads Untouched Human B Cell kit according to manufacturer´s protocol.…”

Section: Methodsmentioning

confidence: 99%

Identification and Characterization of a New Protein Isoform of Human 5-Lipoxygenase

et al. 2016

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Leukotrienes (LTs) are inflammatory mediators that play a pivotal role in many diseases like asthma bronchiale, atherosclerosis and in various types of cancer. The key enzyme for generation of LTs is the 5-lipoxygenase (5-LO). Here, we present a novel putative protein isoform of human 5-LO that lacks exon 4, termed 5-LOΔ4, identified in cells of lymphoid origin, namely the Burkitt lymphoma cell lines Raji and BL41 as well as primary B and T cells. Deletion of exon 4 does not shift the reading frame and therefore the mRNA is not subjected to non-mediated mRNA decay (NMD). By eliminating exon 4, the amino acids Trp144 until Ala184 are omitted in the corresponding protein. Transfection of HEK293T cells with a 5-LOΔ4 expression plasmid led to expression of the corresponding protein which suggests that the 5-LOΔ4 isoform is a stable protein in eukaryotic cells. We were also able to obtain soluble protein after expression in E. coli and purification. The isoform itself lacks canonical enzymatic activity as it misses the non-heme iron but it still retains ATP-binding affinity. Differential scanning fluorimetric analysis shows two transitions, corresponding to the two domains of 5-LO. Whilst the catalytic domain of 5-LO WT is destabilized by calcium, addition of calcium has no influence on the catalytic domain of 5-LOΔ4. Furthermore, we investigated the influence of 5-LOΔ4 on the activity of 5-LO WT and proved that it stimulates 5-LO product formation at low protein concentrations. Therefore regulation of 5-LO by its isoform 5-LOΔ4 might represent a novel mechanism of controlling the biosynthesis of lipid mediators.

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Lipoxin and resolvin biosynthesis is dependent on 5‐lipoxygenase activating protein

Cited by 71 publications

References 45 publications

GM‐CSF– and M‐CSF–primed macrophages present similar resolving but distinct inflammatory lipid mediator signatures

GM‐CSF– and M‐CSF–primed macrophages present similar resolving but distinct inflammatory lipid mediator signatures

Cross-Talk between Cancer Cells and the Tumour Microenvironment: The Role of the 5-Lipoxygenase Pathway

Identification and Characterization of a New Protein Isoform of Human 5-Lipoxygenase

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