15-oxo-Eicosatetraenoic Acid, a Metabolite of Macrophage 15-Hydroxyprostaglandin Dehydrogenase That Inhibits Endothelial Cell Proliferation

Wei, Cong; Zhu, Peijuan; Shah, Sameena; Blair, Ian A.

doi:10.1124/mol.109.057489

Cited by 55 publications

(68 citation statements)

References 46 publications

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“…In addition, 15-LOX1 was also identified as a suppressor of myeloproliferative disease (31). These and other data (32,33) suggest that 15-LOX1 could exert antiproliferative effects and might be associated with generation of antitumor immunity. Consistent with these observations, we could not detect 15-LOX1 expression in tested samples of primary human RCC.…”

Section: Discussionmentioning

confidence: 78%

Tumor-Associated Macrophages Mediate Immunosuppression in the Renal Cancer Microenvironment by Activating the 15-Lipoxygenase-2 Pathway

et al. 2011

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Renal cell carcinoma (RCC), the most common human kidney cancer, is frequently infiltrated with tumorassociated macrophages (TAM) that can promote malignant progression. Here, we show that TAMs isolated from human RCC produce substantial amounts of the proinflammatory chemokine CCL2 and immunosuppressive cytokine IL-10, in addition to enhanced eicosanoid production via an activated 15-lipoxygenase-2 (15-LOX2) pathway. TAMs isolated from RCC tumors had a high 15-LOX2 expression and secreted substantial amounts of 15(S)-hydroxyeicosatetraenoic acid, its major bioactive lipid product. Inhibition of lipoxygenase activity significantly reduced production of CCL2 and IL-10 by RCC TAMs. In addition, TAMs isolated from RCC were capable of inducing in T lymphocytes, the pivotal T regulatory cell transcription factor forkhead box P3 (FOXP3), and the inhibitory cytotoxic T-lymphocyte antigen 4 (CTLA-4) coreceptor. However, this TAMmediated induction of FOXP3 and CTLA-4 in T cells was independent of lipoxygenase and could not be reversed by inhibiting lipoxygenase activity. Collectively, our results show that TAMs, often present in RCCs, display enhanced 15-LOX2 activity that contributes to RCC-related inflammation, immunosuppression, and malignant progression. Furthermore, we show that TAMs mediate the development of immune tolerance through both 15-LOX2-dependent and 15-LOX2-independent pathways. We propose that manipulating LOX-dependent arachidonic acid metabolism in the tumor microenvironment could offer new strategies to block cancer-related inflammation and immune escape in patients with RCC. Cancer Res; 71(20); 6400-9. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 78%

Tumor-Associated Macrophages Mediate Immunosuppression in the Renal Cancer Microenvironment by Activating the 15-Lipoxygenase-2 Pathway

et al. 2011

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“…It is of interest that we found the PGE 2 metabolite tetranor-PGEM rather than PGE 2 . Mfs express 15-hydroxyprostaglandin dehydrogenase (35) and genes for mitochondrial b-oxidation (36, 37); thus, it appears reasonable that tetranor-PGEM could be formed over time in these cell cultures. Also, TxB 2 was abundant in the conditioned media from both Mf types.…”

Section: Discussionmentioning

confidence: 99%

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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“…Therefore, 12(S)-HETE may be a reflection of increased 12/ 15-LOX activity but unrelated to the impact of 12/15-LOX on IL-12 production. Another explanation may lie with the biologically active peroxidated products of 12/15-LOX, such as 12(S)-HpETE, 15(S)-HpETE, and 13(S)-HpODE, or their physiologically active metabolites (54). Moreover, the plethora of recently discovered 12/15-LOX products, such as its phospholipid derivatives (30), or even the ability of 12/15-LOX to generate reactive oxygen species may explain or at least contribute to the regulation of IL-12 production by this enzyme (7,16,32).…”

Section: Discussionmentioning

confidence: 99%

12/15-Lipoxygenase-Dependent Myeloid Production of Interleukin-12 Is Essential for Resistance to Chronic Toxoplasmosis

et al. 2009

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Interleukin-12 (IL-12) is critical for resistance to Toxoplasma gondii during both the acute and chronic stages of infection. However, the cellular and molecular pathways that regulate IL-12 production during chronic toxoplasmosis are incompletely defined. We recently discovered that 12/15-lipoxygenase (12/15-LOX), which oxidizes unsaturated lipids in macrophages, is a novel and selective regulator of IL-12 production. We now demonstrate the essential role of this enzyme in the chronic phase of toxoplasmosis. Although 12/15-LOXdeficient mice were resistant to acute T. gondii infection, 80% of 12/15-LOX-deficient mice died during chronic toxoplasmosis, compared to no deaths in wild-type controls. The morbidity of chronically infected 12/15-LOX mice was associated with an increase in brain inflammation and parasite burden. These data suggest that the evolution of the immune response to T. gondii is accompanied by an increasing requirement for 12/15-LOXmediated signaling. Consistent with this conclusion, 12/15-LOX activity was enhanced during chronic, but not acute, toxoplasmosis. Furthermore, the enhanced susceptibility of 12/15-LOX-deficient mice to chronic toxoplasmosis was associated with reduced production of IL-12 and gamma interferon (IFN-␥) that was not evident during acute infection. Importantly, ex vivo IFN-␥ production by 12/15-LOX-deficient splenocytes could be rescued by the addition of recombinant IL-12. These data establish that 12/15-LOX is a critical mediator of the chronic type 1 inflammatory response and that immune mediators can be subject to distinct cellular and/or molecular mechanisms of regulation at different stages of inflammation.Lipoxygenase and cyclooxygenase families are critical regulators of chronic inflammation that seem to play little role in acute processes (26, 37). Because of this potential specificity, these lipid-metabolizing enzymes have been targeted for years in the search for pathways that selectively impact chronic inflammatory disease. Several studies demonstrated an important role for cyclooxygenase and lipoxygenase products in regulating interleukin-12 (IL-12) production, and lipoxygenases in particular contribute toward the response to Toxoplasma gondii. Specifically, lipoxin A 4 (LxA 4 ), a product of both 15-lipoxygenase (15-LOX) and 5-lipoxygenase (5-LOX) (45), downregulates IL-12 produced by toxoplasma antigen-activated dendritic cells (DCs), thereby tempering the immune response (3,42,57). Indeed, 5-LOX-deficient mice infected with T.

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15-oxo-Eicosatetraenoic Acid, a Metabolite of Macrophage 15-Hydroxyprostaglandin Dehydrogenase That Inhibits Endothelial Cell Proliferation

Cited by 55 publications

References 46 publications

Tumor-Associated Macrophages Mediate Immunosuppression in the Renal Cancer Microenvironment by Activating the 15-Lipoxygenase-2 Pathway

Tumor-Associated Macrophages Mediate Immunosuppression in the Renal Cancer Microenvironment by Activating the 15-Lipoxygenase-2 Pathway

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

12/15-Lipoxygenase-Dependent Myeloid Production of Interleukin-12 Is Essential for Resistance to Chronic Toxoplasmosis

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