Interleukin-4 Induces 15-Lipoxygenase-1 Expression in Human Orbital Fibroblasts from Patients with Graves Disease

Chen, Beiling; Tsui, Shanli; Boeglin, William E.; Douglas, Raymond S.; Brash, Alan R.; Smith, Terry J.

doi:10.1074/jbc.m603484200

Cited by 43 publications

(32 citation statements)

References 55 publications

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“…These results suggest that the induction of activity was not accompanied by a change in the steady state levels of protein. These observations are in agree- ment with interleukin-4 induction of 15-LOX-1 expression in fibroblasts that starts 16 h after cytokine treatment (31). Although it is unclear what mechanisms involved in oxidative stress induce changes 15-LOX-1 activity, the polycystin/lipoxygenase/␣-toxin domain present in lipoxygenases may play a role in this induction (32) and in a possible translocation to the membrane (29).…”

Section: Discussionsupporting

confidence: 76%

Selective Survival Rescue in 15-Lipoxygenase-1-deficient Retinal Pigment Epithelial Cells by the Novel Docosahexaenoic Acid-derived Mediator, Neuroprotectin D1

Calandria

Marcheselli

Mukherjee

et al. 2009

Journal of Biological Chemistry

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The integrity of the retinal pigment epithelial (RPE) cell is essential for the survival of rod and cone photoreceptor cells. Several stressors, including reactive oxygen species, trigger apoptotic damage in RPE cells preceded by an anti-inflammatory, pro-survival response, the formation of neuroprotectin D1 (NPD1), an oxygenation product derived from the essential omega-3 fatty acid family member docosahexaenoic acid. To define the ability of NPD1 and other endogenous novel lipid mediators in cell survival, we generated a stable knockdown human RPE (ARPE-19) cell line using short hairpin RNA to target 15-lipoxygenase-1. The 15-lipoxygenase-1-deficient cells exhibited 30% of the protein expression, and 15-lipoxygenase-2 remained unchanged, as compared with an ARPE-19 cell line control established using nonspecific short hairpin RNA transfected cells. NPD1 synthesis was stimulated by tumor necrosis factor ␣/H 2 O 2 -mediated oxidative stress in nonspecific cells (controls), whereas in silenced cells, negligible amounts of NPD1, 12(S)-and 15(S)-hydroxyeicosatetraenoic acid, and lipoxin A 4 were found under these conditions. Neither control nor the deficient cells showed an increase in 15-lipoxygenase-1 protein content after 16 h of oxidative stress, suggesting that the increased activity of 15-lipoxygenase-1 is due to activation of pre-existing proteins. 15-Lipoxygenase-silenced cells also displayed an exacerbated sensitivity to oxidative stress-induced apoptosis when compared with the control cells. NPD1 selectively and potently rescued 15-lipoxygenase-silenced cells from oxidative stress-induced apoptosis. These results demonstrate that 15-lipoxygenase-1 is activated by oxidative stress in ARPE-19 cells and that NPD1 is part of an early survival signaling in RPE cells. Retinal pigment epithelial (RPE)2 cells are essential for the survival of rod and cone photoreceptors. RPE cells mediate the renewal of photoreceptor outer segments (1, 2); synthesis and secretion of neurotrophins (3); recycling of bleached visual pigments; and transport of vitamin A (4), docosahexaenoic acid (DHA), and other nutrients, and ions and fluids between photoreceptors and the choriocapillaries (5). Failure of RPE cells to accomplish their functions leads to photoreceptor damage or death and, as a consequence, decreased vision and eventually blindness. Apoptotic cell death of RPE cells takes place in retinal degenerative diseases, including retinitis pigmentosa and age-related macular degeneration; as a result, photoreceptors degenerate (6, 7).Cell fate decisions made at the ectoderm yield either neuronal progeny or RPE cells. Thus RPE cells display similarities to neuronal lineages, even when differentiated (8), that make them suitable for conversion into neurons for therapeutic purposes (9). For example, recent studies revealed mechanisms for the transdifferentiation of RPE cells that depend on the expression status of certain genes (10). These studies have created a new interest in RPE cells caused by the potential applications not on...

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Section: Discussionsupporting

confidence: 76%

Selective Survival Rescue in 15-Lipoxygenase-1-deficient Retinal Pigment Epithelial Cells by the Novel Docosahexaenoic Acid-derived Mediator, Neuroprotectin D1

Calandria

Marcheselli

Mukherjee

et al. 2009

Journal of Biological Chemistry

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“…In agreement with previous results, [2][3][4]7,8,35,36 microarray analysis showed that IL-4 induced a restricted set of genes in human macrophages (204 genes; 0.7% of the transcriptome), 45.6% of which were significantly affected by pretreatment with 10058-F4. Therefore, microarray results indicate that alternative activation genes can be classified as c-MYC dependent (Figure 2) or c-MYC independent (supplemental Figure 1) according to the role of the c-MYC transcription factor in their induction during alternative macrophage activation.…”

Section: C-myc Is Involved In the Expression Of A Distinct Subset Of supporting

confidence: 79%

“…38 Conversely, ALOX15 induction by IL-4 in various cell types, including primary cultures of human monocytes, had been suggested previously to be a STAT6-dependent event. 45,46 Nonetheless, in T-cell lymphoma cells, histone deacetylase inhibitors able to reduce STAT6 and phospho-STAT6 protein expression did not affect ALOX15 expression, 47 suggesting the existence of STAT6-independent intracellular pathways regulating ALOX15 expression in response to IL-4. Similarly, MRC1 induction by IL-4 in macrophages and dendritic cells has been well established.…”

Section: Discussionmentioning

confidence: 99%

Role of c-MYC in alternative activation of human macrophages and tumor-associated macrophage biology

Pello¹,

Pizzol²,

Mirolo³

et al. 2012

Blood

312

268

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In response to microenvironmental signals, macrophages undergo different activation, including the "classic" proinflammatory phenotype (also called M1), the "alternative" activation induced by the IL-4/IL-13 trigger, and the related but distinct heterogeneous M2 polarization associated with the anti-inflammatory profile. The latter is induced by several stimuli, including IL-10 and TGF-␤. Macrophagepolarized activation has profound effects on immune and inflammatory responses and in tumor biology, but information on the underlying molecular pathways is scarce. In the present study, we report that alternative polarization of macrophages requires the transcription factor c-MYC. In macrophages, IL-4 and different stimuli sustaining M2-like polarization induce c-MYC expression and its translocation to the nucleus. c-MYC controls the induction of a subset (45%) of genes associated with alternative activation. ChIP assays indicate that c-MYC directly regulates some genes associated with alternative activation, including SCARB1, ALOX15, and MRC1, whereas others, including CD209, are indirectly regulated by c-MYC. c-MYC up-regulates the IL-4 signaling mediators signal transducer and activator of transcription-6 and peroxisome proliferator-activated receptor␥, is also expressed in tumorassociated macrophages, and its inhibition blocks the expression of protumoral genes including VEGF, MMP9, HIF-1␣, and TGF-␤. We conclude that c-MYC is a key player in alternative macrophage activation, and is therefore a potential therapeutic target in pathologies related to these cells, including tumors. (Blood. 2012;119(2):411-421) IntroductionMacrophages are specialized phagocytic cells involved in multiple processes, both in homeostatic conditions and during the immune response after tissue damage or exposure to a pathogen. Macrophages are characterized by a striking heterogeneity, which can be partially ascribed to their origin by self-renewal of resident postmitotic cells and by monocyte subsets recruited and differentiated locally. 1-3 A second element shaping macrophage heterogeneity is the microenvironment, both under homeostatic conditions, with the hosting tissue profoundly influencing macrophage differentiation, and in the context of an inflammatory or immune response, which generates a wide range of polarized activation states. [3][4][5][6] Activation with IFN-␥, alone or in combination with pathogen-derived signals such as lipopolysaccharide (LPS), leads to classically activated macrophages, also referred to as M1 cells, which develop proinflammatory type 1 immune responses. Macrophage exposure to other immune signals results in profoundly different functional phenotypes. These include "alternatively activated" macrophages caused by IL-4/IL-13 stimulation, which are associated with type 2 immune responses and a spectrum of functional phenotypes related to anti-inflammatory, angiogenic, and tissue-repair properties induced in macrophages by stimuli including TGF-␤, immune complexes, glucocorticoids, and IL-10. 3,4,6,7 Further...

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“…Although significant differences in cell number were not evident in stained peripheral blood smears, this would not have been sensitive enough to detect functional changes in the leukocytes. Although little information is available about the direct regulation of 15-LO by corticosteroids, the induction of 15-LO-1 expression in vitro by IL-4 and IL-13 can be attenuated by steroids in orbital fibroblasts (47). COX-2 expression was downregulated in all samples from subjects with severe asthma.…”

Section: Discussionmentioning

confidence: 96%

Airway Lipoxin A₄Generation and Lipoxin A₄Receptor Expression Are Decreased in Severe Asthma

Planagumà

Kazani

Marigowda

et al. 2008

Am J Respir Crit Care Med

216

194

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Rationale: Airway inflammation is common in severe asthma despite antiinflammatory therapy with corticosteroids. Lipoxin A 4 (LXA 4 ) is an arachidonic acid-derived mediator that serves as an agonist for resolution of inflammation. Objectives: Airway levels of LXA 4 , as well as the expression of lipoxin biosynthetic genes and receptors, in severe asthma. Methods: Samples of bronchoalveolar lavage fluid were obtained from subjects with asthma and levels of LXA 4 and related eicosanoids were measured. Expression of lipoxin biosynthetic genes was determined in whole blood, bronchoalveolar lavage cells, and endobronchial biopsies by quantitative polymerase chain reaction, and leukocyte LXA 4 receptors were monitored by flow cytometry. Measurements and Main Results: Individuals with severe asthma had significantly less LXA 4 in bronchoalveolar lavage fluids (11.2 6 2.1 pg/ml) than did subjects with nonsevere asthma (150.1 6 38.5 pg/ml; P , 0.05). In contrast, levels of cysteinyl leukotrienes were increased in both asthma cohorts compared with healthy individuals. In severe asthma, 15-lipoxygenase-1 mean expression was decreased fivefold in bronchoalveolar lavage cells. In contrast, 15-lipoxgenase-1 was increased threefold in endobronchial biopsies, but expression of both 5-lipoxygenase and 15-lipoxygenase-2 in these samples was decreased. Cyclooxygenase-2 expression was decreased in all anatomic compartments sampled in severe asthma. Moreover, LXA 4 receptor gene and protein expression were significantly decreased in severe asthma peripheral blood granulocytes. Conclusions: Mechanisms underlying pathological airway responses in severe asthma include lipoxin underproduction with decreased expression of lipoxin biosynthetic enzymes and receptors. Together, these results indicate that severe asthma is characterized, in part, by defective lipoxin counterregulatory signaling circuits.

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Interleukin-4 Induces 15-Lipoxygenase-1 Expression in Human Orbital Fibroblasts from Patients with Graves Disease

Cited by 43 publications

References 55 publications

Selective Survival Rescue in 15-Lipoxygenase-1-deficient Retinal Pigment Epithelial Cells by the Novel Docosahexaenoic Acid-derived Mediator, Neuroprotectin D1

Selective Survival Rescue in 15-Lipoxygenase-1-deficient Retinal Pigment Epithelial Cells by the Novel Docosahexaenoic Acid-derived Mediator, Neuroprotectin D1

Role of c-MYC in alternative activation of human macrophages and tumor-associated macrophage biology

Airway Lipoxin A₄Generation and Lipoxin A₄Receptor Expression Are Decreased in Severe Asthma

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Interleukin-4 Induces 15-Lipoxygenase-1 Expression in Human Orbital Fibroblasts from Patients with Graves Disease

Cited by 43 publications

References 55 publications

Selective Survival Rescue in 15-Lipoxygenase-1-deficient Retinal Pigment Epithelial Cells by the Novel Docosahexaenoic Acid-derived Mediator, Neuroprotectin D1

Selective Survival Rescue in 15-Lipoxygenase-1-deficient Retinal Pigment Epithelial Cells by the Novel Docosahexaenoic Acid-derived Mediator, Neuroprotectin D1

Role of c-MYC in alternative activation of human macrophages and tumor-associated macrophage biology

Airway Lipoxin A4Generation and Lipoxin A4Receptor Expression Are Decreased in Severe Asthma

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Airway Lipoxin A₄Generation and Lipoxin A₄Receptor Expression Are Decreased in Severe Asthma