Expression and regulation of 12/15-lipoxygenases in human primary macrophages

Wuest, Sophia J.A.; Crucet, Margot; Gemperle, Corinne; Loretz, Christa; Hersberger, Martin

doi:10.1016/j.atherosclerosis.2012.07.022

Cited by 60 publications

(64 citation statements)

References 34 publications

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“…Although ALOX5 expression is suppressed in IL-4-stimulated cells, both ALOX15 and ALOX15B are induced. Although ALOX15B is detectable at the protein level in resting macrophages, which corroborates an earlier report (13), only stimulation with IL-4 initiates the production of substantial amounts of the 15-lipoxygenase metabolites 12(S)-HETE and 15(S)-HETE, which is antagonized either by silencing ALOX15 or activating AMPK. Therefore, ALOX15 is the predominant lipoxygenase isoform producing 12(S)-HETE and 15(S)-HETE in IL-4-polarized macrophages.…”

Section: Discussionsupporting

confidence: 72%

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AMP-activated Protein Kinase Suppresses Arachidonate 15-Lipoxygenase Expression in Interleukin 4-polarized Human Macrophages

Namgaladze

Snodgrass

Angioni

et al. 2015

Journal of Biological Chemistry

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Background: How AMP-activated protein kinase (AMPK) influences IL-4-induced human macrophage polarization is not completely understood. Results: AMPK prevents arachidonate 15-lipoxygenase induction by IL-4 and abolishes the formation of 15-lipoxygenase arachidonic acid metabolites. Conclusion: AMPK activation promotes an anti-inflammatory phenotype in IL-4-stimulated macrophages by reducing arachidonate 15-lipoxygenase expression. Significance: This study supports an anti-inflammatory effect of AMPK activation.

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Section: Discussionsupporting

confidence: 72%

“…Whether ALOX15 exerts additional roles in IL-4/IL-13 macro-phage polarization is unknown. Human macrophages also constitutively express ALOX15B, an isoform of arachidonate 15-lipoxygenase (13). This isoform is induced by hypoxia (14) and produces T cell-attractive chemokines in macrophages (15).…”

mentioning

confidence: 99%

AMP-activated Protein Kinase Suppresses Arachidonate 15-Lipoxygenase Expression in Interleukin 4-polarized Human Macrophages

Namgaladze

Snodgrass

Angioni

et al. 2015

Journal of Biological Chemistry

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“…To investigate whether RvE1 causes a repolarization of inflammatory M1 macrophages, we sequentially stimulated primary human macrophages with LPS followed by the stimulation with RvE1, and characterized the polarization phenotype of these macrophages. As expected, LPS-stimulated M1 macrophages exhibited an increased transcription of IL-1b, TNF-a, and cell-surface expression of CD80 and CD206 (mannose receptor) (30,35), which returned to levels comparable with untreated macrophages upon removal of the stimulus for 4 d (data not shown). Sequential stimulation of these M1 macrophages with 10 nM RvE1 at day 1 of the 4-d incubation did not alter transcription for IL-1b and TNF-a, or cell-surface expression for ChemR23 and CD206 (Fig.…”

Section: Rve1 Repolarizes Human M1 Macrophagesmentioning

confidence: 71%

ChemR23, the Receptor for Chemerin and Resolvin E1, Is Expressed and Functional on M1 but Not on M2 Macrophages

Herová

Schmid

Gemperle

et al. 2015

The Journal of Immunology

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133

100

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ChemR23 is a G protein–coupled receptor that is triggered by two ligands, the peptide chemerin and the eicosapentaenoic acid–derived lipid mediator resolvin E1 (RvE1). Chemerin acts as a chemoattractant for monocytes and macrophages, whereas RvE1 promotes resolution of inflammation-inducing macrophage phagocytosis of apoptotic neutrophils. Although ChemR23-mediated signaling plays a role in mononuclear cell migration to inflamed tissue, as well as in the resolution of inflammation, its regulation in different polarization states of macrophages is largely unknown. We analyzed the expression and function of ChemR23 in monocytes and differently activated human primary macrophages. Using 5′ RACE, we identified three transcription start sites and several splice variants of ChemR23 in both monocytes and macrophages. Although the promoters P1 and P3 are used equally in unpolarized macrophages, stimulation with LPS or IFN-γ leads to increased transcription from P3 in inflammatory M1 macrophages. Such ChemR23-expressing M1 macrophages are chemotactic to chemerin, whereas M2 macrophages not expressing ChemR23 surface receptor are not. Repolarization of ChemR23-expressing M1 macrophages with 10 nM RvE1 increases IL-10 transcription and phagocytosis of microbial particles, leading to a resolution-type macrophage distinct from the M2 phenotype. These results show that ChemR23 is tightly regulated in response to inflammatory and anti-inflammatory stimuli. The restricted expression of ChemR23 in naive and M1 macrophages supports the role of ChemR23 in the attraction of macrophages to inflamed tissue by chemerin and in the initiation of resolution of inflammation through RvE1-mediated repolarization of human M1 macrophages toward resolution-type macrophages.

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“…Recent data implicate the 15-LOX-2 isoform in the pathogenesis of atherosclerosis because mRNA and protein levels of this LOX have been shown to be high in human carotid plaques (6). In addition, 15-LOX-2 is expressed in macrophages (7,34,35), and expression is regulated by hypoxia-inducible factor-1␣ (35). Moreover, knockdown of 15-LOX-2 expression in human primary macrophages and in mice (in this case, the target was 8-LOX, the murine homologue of 15-LOX-2) decreased lipid accumulation and inflammation, hallmarks of atherosclerosis (8).…”

Section: Discussionmentioning

confidence: 99%

“…Mouse knock-out studies with the LOX homologue of 15-LOX-1 support a role for ALOX15A in plaque formation (5). However, it is ALOX15B mRNA that is present in human macrophages (6,7) isolated from atherosclerotic plaques. Furthermore, elevated levels of ALOX15B mRNA are present in carotid lesions derived from symptomatic, rather than asymptomatic, subjects.…”

mentioning

confidence: 99%

The Structure of Human 15-Lipoxygenase-2 with a Substrate Mimic

Kobe

Neau

Mitchell

et al. 2014

Journal of Biological Chemistry

111

146

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Background: 15-Lipoxygenase-2 is linked to atherosclerotic plaque formation; the homologous enzyme 5-lipoxygenase initiates the synthesis of proinflammatory leukotrienes. Results: We determined the crystal structure of 15-LOX-2 in the presence of a substrate mimic. Conclusion: 15-Lipoxygenase-2 and 5-lipoxgenase display active site variations that confer distinct product specificities. Significance: These differences can be exploited for the design of isoform-specific anti-inflammatories.

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Expression and regulation of 12/15-lipoxygenases in human primary macrophages

Cited by 60 publications

References 34 publications

AMP-activated Protein Kinase Suppresses Arachidonate 15-Lipoxygenase Expression in Interleukin 4-polarized Human Macrophages

AMP-activated Protein Kinase Suppresses Arachidonate 15-Lipoxygenase Expression in Interleukin 4-polarized Human Macrophages

ChemR23, the Receptor for Chemerin and Resolvin E1, Is Expressed and Functional on M1 but Not on M2 Macrophages

The Structure of Human 15-Lipoxygenase-2 with a Substrate Mimic

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