Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

When human monocytes or alveolar macrophages are cultured in the presence of interleukin (IL)-4 or IL-13, the expression of the reticulocyte-type 15-lipoxygenase is induced. In mice a 15-lipoxygenase is not expressed, but a leukocyte-type 12-lipoxygenase is present in peritoneal macrophages. To investigate whether both lipoxygenase isoforms exhibit a similar regulatory response toward cytokine stimulation, we studied the regulation of the leukocyte-type 12-lipoxygenase of murine peritoneal macrophages by interleukins and found that the activity of this enzyme is upregulated in a dose-dependent manner when the cells were cultured in the presence of the IL-4 or IL-13 but not by IL-10. When peripheral murine monocytes that do not express the lipoxygenase were treated with IL-4 expression of 12/15-lipoxygenase mRNA was induced, suggesting pretranslational control mechanisms. In contrast, no upregulation of the lipoxygenase activity was observed when the macrophages were prepared from homozygous STAT6-deficient mice. Peritoneal macrophages of transgenic mice that systemically overexpress IL-4 exhibited a threefold to fourfold higher 12-lipoxygenase activity than cells prepared from control animals. A similar upregulation of 12-lipoxygenase activity was detected in heart, spleen, and lung of the transgenic animals. Moreover, a strong induction of the enzyme was observed in red cells during experimental anemia in mice. The data presented here indicate that (1) the 12-lipoxygenase activity of murine macrophages is upregulated in vitro and in vivo by IL-4 and/or IL-13, (2) this upregulation requires expression of the transcription factor STAT6, and (3) the constitutive expression of the enzyme appears to be STAT6 independent. The cytokine-dependent upregulation of the murine macrophage 12-lipoxygenase and its induction during experimental anemia suggests its close relatedness with the human reticulocyte-type 15-lipoxygenase despite their differences in the positional specificity of arachidonic acid oxygenation.
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PMID:Interleukin-4 and -13 induce upregulation of the murine macrophage 12/15-lipoxygenase activity: evidence for the involvement of transcription factor STAT6. 974 91

In mammalian cells, enzymatic lipid peroxidation catalyzed by 12/15-lipoxygenases is regulated by pretranslational, translational, and posttranslational processes. In rabbits, rats, and mice induction of experimental anemia leads to a systemic up-regulation of 12/15-lipoxygenases expression. In addition, interleukins-4 and -13 were identified as strong up-regulators of this enzyme in human and murine monocyte/macrophages and in the lung carcinoma cell line A549, and the interleukin-4(13) cell surface receptor as well as the signal transducer and activator of transcription 6 (STATG) appears to be involved in the signal transduction cascade. On the level of translation, 15-lipoxygenase synthesis is blocked by the binding of regulatory proteins to a characteristic guanine-cytosine-rich repetitive element in the 3'-untranslated region of the rabbit 15-lipoxygenase mRNA, and the formation of such 15-lipoxygenase mRNA/protein complexes was identified as molecular reason for the translational inactivity of the 15-lipoxygenase mRNA in immature red blood cells. However, proteolytic breakdown of the regulatory proteins which were recently identified as hnRNP K and hnRNP E1 overcomes translational inhibition during later stages of reticulocyte maturation. For maximal intracellular activity, 12/15-lipoxygenases require a rise in cytosolic calcium concentration inducing a translocation of the enzyme from the cytosol to cellular membranes as well as small amounts of preformed hydroperoxides which act as essential activators of the enzymes. 12/15-Lipoxygenases undergo irreversible suicide inactivation during fatty acid oxygenation, and this process may be considered an element of down-regulation of enzyme activity. Suicide inactivation and proteolytic breakdown may contribute to the disappearance of functional 12/15-lipoxygenase at later stages of erythropoiesis.
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PMID:Regulation of cellular 15-lipoxygenase activity on pretranslational, translational, and posttranslational levels. 1041 77

Glutathione peroxidase 4 (GPX4) is unique as it is the only enzyme that can prevent detrimental lipid peroxidation in vivo by reducing lipid peroxides to the respective alcohols thereby stabilizing oxidation products of unsaturated fatty acids. During reticulocyte maturation, lipid peroxidation mediated by 15-lipoxygenase in humans and rabbits and by 12/15-lipoxygenase (ALOX15) in mice was considered the initiating event for the elimination of mitochondria but is now known to occur through mitophagy. Yet, genetic ablation of the Alox15 gene in mice failed to provide evidence for this hypothesis. We designed a different genetic approach to tackle this open conundrum. Since either other lipoxygenases or non-enzymatic autooxidative mechanisms may compensate for the loss of Alox15, we asked whether ablation of Gpx4 in the hematopoietic system would result in the perturbation of reticulocyte maturation. Quantitative assessment of erythropoiesis indices in the blood, bone marrow (BM) and spleen of chimeric mice with Gpx4 ablated in hematopoietic cells revealed anemia with an increase in the fraction of erythroid precursor cells and reticulocytes. Additional dietary vitamin E depletion strongly aggravated the anemic phenotype. Despite strong extramedullary erythropoiesis reticulocytes failed to mature and accumulated large autophagosomes with engulfed mitochondria. Gpx4-deficiency in hematopoietic cells led to systemic hepatic iron overload and simultaneous severe iron demand in the erythroid system. Despite extremely high erythropoietin and erythroferrone levels in the plasma, hepcidin expression remained unchanged. Conclusively, perturbed reticulocyte maturation in response to Gpx4 loss in hematopoietic cells thus causes ineffective erythropoiesis, a phenotype partially masked by dietary vitamin E supplementation.
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PMID:Glutathione peroxidase 4 and vitamin E control reticulocyte maturation, stress erythropoiesis and iron homeostasis. 3124 67