HIF-1α regulates IL-1β and IL-17 in sarcoidosis
| Autor: | Harvinder Talwar, Christian Bauerfeld, Lobelia Samavati, Kezhong Zhang, Paul Tranchida, Lawrence I. Grossman, Jaya Talreja |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Small interfering RNA medicine.medical_treatment Interleukin-1beta Monocytes Immunology and Inflammation 0302 clinical medicine Biology (General) Lung biology Chemistry General Neuroscience Interleukin-17 General Medicine 3. Good health IL-17 Cytokine Hypoxia-inducible factors IL-1β 030220 oncology & carcinogenesis Medicine Female medicine.symptom Research Article Adult Adolescent Sarcoidosis QH301-705.5 Science CD14 HIF-1α Inflammation In situ hybridization General Biochemistry Genetics and Molecular Biology Young Adult 03 medical and health sciences Downregulation and upregulation None medicine Humans Human Biology and Medicine General Immunology and Microbiology Macrophages alveolar macrophages Th1 Cells Hypoxia-Inducible Factor 1 alpha Subunit 030104 developmental biology Gene Expression Regulation Cancer research biology.protein Th17 Cells GLUT1 |
| Zdroj: | eLife eLife, Vol 8 (2019) |
| ISSN: | 2050-084X |
| Popis: | Sarcoidosis is a complex systemic granulomatous disease of unknown etiology characterized by the presence of activated macrophages and Th1/Th17 effector cells. Data mining of our RNA-Seq analysis of CD14+monocytes showed enrichment for metabolic and hypoxia inducible factor (HIF) pathways in sarcoidosis. Further investigation revealed that sarcoidosis macrophages and monocytes exhibit higher protein levels for HIF-α isoforms, HIF-1β, and their transcriptional co-activator p300 as well as glucose transporter 1 (Glut1). In situ hybridization of sarcoidosis granulomatous lung tissues showed abundance of HIF-1α in the center of granulomas. The abundance of HIF isoforms was mechanistically linked to elevated IL-1β and IL-17 since targeted down regulation of HIF-1α via short interfering RNA or a HIF-1α inhibitor decreased their production. Pharmacological intervention using chloroquine, a lysosomal inhibitor, decreased lysosomal associated protein 2 (LAMP2) and HIF-1α levels and modified cytokine production. These data suggest that increased activity of HIF-α isoforms regulate Th1/Th17 mediated inflammation in sarcoidosis. eLife digest Sarcoidosis is a rare disease that is characterized by the formation of small lumps known as granulomas inside the body. These lumps are made up of clusters of immune cells, and are commonly found in the skin, lung or eye. Other organs of the body can also be affected, and symptoms will vary depending on where in the body lumps form. There is currently no specific treatment for sarcoidosis, as the direct cause of the disease is unknown. The disease is often treated with drugs that suppress the immune system. However, this type of treatment can lead to significant side effects and patients will respond to these drugs in different ways. Patients with sarcoidosis have a heightened immune response to microbes that can cause infections, and rather than providing protection, this heightened response causes damage and inflammation to the body’s organs. Now, Talreja et al. have identified which genes and proteins control this inflammatory response in immune cells from the lungs and blood of sarcoidosis patients. Immune cells in the lungs of sarcoidosis patients were found to have higher levels of hypoxia inducible factor (HIF) – a gene-regulating protein that controls the uptake and metabolism of oxygen in mammals. In addition, lung tissue affected with granulomas also expressed increased levels of a specific version of HIF known as HIF-1. Talreja et al. showed that the increased expression of HIF in the immune cells of sarcoidosis patients was mechanistically linked to the production of several molecules that promote inflammation. Inhibiting HIF-1 led to a decrease in the production of these inflammatory molecules, indicating that increased activity of HIF-1 causes inflammation in sarcoidosis patients. It remains unclear what causes this abundance of HIF-1α. It is possible that specific modifications of this factor prevent it from degrading, resulting in higher levels. By identifying a link between HIF-1 and inflammation, these findings open up potential new avenues of the treatment for sarcoidosis patients. |
| Databáze: | OpenAIRE |
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