Myeloid cell expression of the RNA-binding protein HuR protects mice from pathologic inflammation and colorectal carcinogenesis
| Autor: | Marios Dimitriou, Christina Eftychi, Anthie Yiakouvaki, Ioannis Karakasiliotis, Dimitris L. Kontoyiannis, Stamatis Theocharis |
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| Rok vydání: | 2010 |
| Předmět: |
CCR2
Myeloid Mice 129 Strain Inflammation Biology Macrophage chemotaxis 03 medical and health sciences Mice 0302 clinical medicine medicine Gene silencing Animals Myeloid Cells RNA Messenger RNA Processing Post-Transcriptional 030304 developmental biology Mice Knockout 0303 health sciences Innate immune system Endosomal Sorting Complexes Required for Transport General Medicine Macrophage Activation Colitis Endotoxemia Immunity Innate 3. Good health DNA-Binding Proteins Mice Inbred C57BL Interleukin 10 medicine.anatomical_structure ELAV Proteins 030220 oncology & carcinogenesis Immunology Cancer research Disease Progression Commentary Cytokines Tumor necrosis factor alpha medicine.symptom Inflammation Mediators Colorectal Neoplasms Signal Transduction Transcription Factors |
| Zdroj: | Journal of Clinical Investigation; Vol 122 |
| ISSN: | 1558-8238 |
| Popis: | The innate immune response involves a variety of inflammatory reactions that can result in inflammatory disease and cancer if they are not resolved and instead are allowed to persist. The effective activation and resolution of innate immune responses relies on the production and posttranscriptional regulation of mRNAs encoding inflammatory effector proteins. The RNA-binding protein HuR binds to and regulates such mRNAs, but its exact role in inflammation remains unclear. Here we show that HuR maintains inflammatory homeostasis by controlling macrophage plasticity and migration. Mice lacking HuR in myeloid-lineage cells, which include many of the cells of the innate immune system, displayed enhanced sensitivity to endotoxemia, rapid progression of chemical-induced colitis, and severe susceptibility to colitis-associated cancer. The myeloid cell–specific HuR-deficient mice had an exacerbated inflammatory cytokine profile and showed enhanced CCR2-mediated macrophage chemotaxis. At the molecular level, activated macrophages from these mice showed enhancements in the use of inflammatory mRNAs (including Tnf, Tgfb, Il10, Ccr2, and Ccl2) due to a lack of inhibitory effects on their inducible translation and/or stability. Conversely, myeloid overexpression of HuR induced posttranscriptional silencing, reduced inflammatory profiles, and protected mice from colitis and cancer. Our results highlight the role of HuR as a homeostatic coordinator of mRNAs that encode molecules that guide innate inflammatory effects and demonstrate the potential of harnessing the effects of HuR for clinical benefit against pathologic inflammation and cancer. |
| Databáze: | OpenAIRE |
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