RIPK1 Inhibitor Ameliorates Colitis by Directly Maintaining Intestinal Barrier Homeostasis and Regulating Following IECs-IMMUNO Crosstalk
| Autor: | Yanwei Wu, Chen Fan, Qing Qi, Chunlan Feng, Huimin Lu, Heng Li, Wei Tang, Yu-xi Yan, Jianping Zuo, Bing Wu, Yuanzhuo Gao |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Chemokine Necroptosis Regulator Biochemistry 03 medical and health sciences RIPK1 chemistry.chemical_compound Mice 0302 clinical medicine Immune system Cell Line Tumor Animals Homeostasis Humans Intestinal Mucosa Barrier function Pharmacology biology Tight junction NF-κB Epithelial Cells Triazoles Colitis Cell biology Intestines Mice Inbred C57BL Oxazepines 030104 developmental biology chemistry Gene Expression Regulation 030220 oncology & carcinogenesis Receptor-Interacting Protein Serine-Threonine Kinases biology.protein |
| Zdroj: | SSRN Electronic Journal. |
| ISSN: | 1556-5068 |
| Popis: | Background The receptor-interacting protein kinase 1 (RIPK1) has emerged as a key upstream regulator that controls the inflammatory response via its kinase-dependent and independent functions, which makes it an attractive target for developing new drugs against inflammation-related diseases. Growing evidences illustrate that RIPK1 is certainly associated with pathogenesis of multiple tissue-damage diseases. However, what are intricate regulatory codes of RIPK1 inhibitor in diseases is still obscure. Methods We used DSS-induced colitis model in vivo to study the therapeutic effects and the mechanisms of RIPK1 inhibitor. We next characterized the barrier function and the interaction between intestinal epithelial cells (IECs) and immunocytes both in vivo and in vitro. As a candidate in clinical study, GSK2982772 is the most well-developed drug of RIPK1 inhibitors, and we chose it as our study object. Results We demonstrated that RIPK1 inhibitor could ameliorate the intestinal barrier injury by reducing tight junctions’ disruption and accompanying oxidative stress. Moreover, the release of chemokines and adhesion molecules from damaged IECs was suppressed by RIPK1 inhibitor treatment. And these protective effects were not only dependent on the suppression of necroptosis but also on the compromised activity of NF-κB. Taken together, RIPK1 inhibitor exerts suppressive function in intestinal inflammatory response possibly via protecting the intestinal epithelial barrier and maintaining the homeostasis of immune microenvironments. Eventually, the positive feedback immune response which triggered progressive epithelial cells injury could be restrained. |
| Databáze: | OpenAIRE |
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