Triggering ubiquitination of IFNAR1 protects tissues from inflammatory injury
| Autor: | Angela K Brice, N. Adrian Leu, Anil K. Rustgi, Hallgeir Rui, Bin Zhao, Hui Zheng, Kelly A. McCorkell, Melanie A. Girondo, Shigetsugu Takano, Kanstantsin V. Katlinski, Narayan G. Avadhani, Sabyasachi Bhattacharya, Yuliya V. Katlinskaya, Michael J. May, Serge Y. Fuchs, Qiujing Yu, Satish Srinivasan, Christopher J. Carbone, Maximilian Reichert |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Medicine (General)
receptor Interleukin-1beta pancreatitis Endogeny Inflammation Receptor Interferon alpha-beta QH426-470 Mice R5-920 Downregulation and upregulation Ubiquitin Interferon medicine Genetics Animals Regeneration hepatitis Gene Knock-In Techniques Pancreas Research Articles Bone Marrow Transplantation biology Interleukin-6 Tumor Necrosis Factor-alpha Regeneration (biology) Wild type Ubiquitination interferon 3. Good health Mice Inbred C57BL Liver inflammation Immunology Acute Disease Chronic Disease Cancer research biology.protein Molecular Medicine Tumor necrosis factor alpha Female medicine.symptom Chemical and Drug Induced Liver Injury medicine.drug |
| Zdroj: | EMBO Molecular Medicine, Vol 6, Iss 3, Pp 384-397 (2014) EMBO Molecular Medicine |
| ISSN: | 1757-4676 1757-4684 |
| Popis: | Type 1 interferons (IFN) protect the host against viruses by engaging a cognate receptor (consisting of IFNAR1/IFNAR2 chains) and inducing downstream signaling and gene expression. However, inflammatory stimuli can trigger IFNAR1 ubiquitination and downregulation thereby attenuating IFN effects in vitro . The significance of this paradoxical regulation is unknown. Presented here results demonstrate that inability to stimulate IFNAR1 ubiquitination in the Ifnar1SA knock‐in mice renders them highly susceptible to numerous inflammatory syndromes including acute and chronic pancreatitis, and autoimmune and toxic hepatitis. Ifnar1SA mice (or their bone marrow‐receiving wild type animals) display persistent immune infiltration of inflamed tissues, extensive damage and gravely inadequate tissue regeneration. Pharmacologic stimulation of IFNAR1 ubiquitination is protective against from toxic hepatitis and fulminant generalized inflammation in wild type but not Ifnar1SA mice. These results suggest that endogenous mechanisms that trigger IFNAR1 ubiquitination for limiting the inflammation‐induced tissue damage can be purposely mimicked for therapeutic benefits. ![][1] Inflammatory process in response to injury starts by inducing tissue damage followed by resolution of inflammation. Here, endogenous or induced IFNAR1 ubiquitination and degradation are shown to limit the extent of tissue damage and accelerate healing. EMBO Mol Med (2014) 6, 384–397 [1]: /embed/graphic-1.gif |
| Databáze: | OpenAIRE |
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