Inhibition of the TIRAP-c-Jun interaction as a therapeutic strategy for AP1-mediated inflammatory responses
| Autor: | Burak Kizil, Mansi Srivastava, Kishore K. Wary, Sreeparna Banerjee, Mirza S. Baig, Kannan Muthu, Uzma Saqib |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Lipopolysaccharides
Male 0301 basic medicine TIRAP Lipopolysaccharide Proto-Oncogene Proteins c-jun Immunology Inflammation Pharmacology Proinflammatory cytokine Sepsis Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Gefitinib medicine Animals Humans Immunology and Allergy Molecular Targeted Therapy Protein Kinase Inhibitors Cells Cultured Membrane Glycoproteins business.industry Macrophages c-jun Receptors Interleukin-1 medicine.disease Molecular Docking Simulation Toll-Like Receptor 4 Transcription Factor AP-1 Disease Models Animal AP-1 transcription factor 030104 developmental biology chemistry 030220 oncology & carcinogenesis medicine.symptom business Protein Binding Signal Transduction medicine.drug |
| Zdroj: | International Immunopharmacology. 71:188-197 |
| ISSN: | 1567-5769 |
| Popis: | Bacterial endotoxin-induced sepsis causes 30–40% of the deaths in the intensive care unit (ICU) globally, for which there is no pharmacotherapy. Lipopolysaccharide (LPS), a bacterial endotoxin, stimulates the Toll-like receptor (TLR)-4 signalling pathways to upregulate the expression of various inflammatory mediators. Here, we show that the TIRAP and c-Jun protein signalling complex forms in macrophages in response to LPS stimulation, which increases the AP1 transcriptional activity, thereby amplifying the expression of inflammatory mediators. Using a computer-aided molecular docking platform, we identified gefitinib as a putative inhibitor of the TIRAP-c-Jun signalling complex. Further, we demonstrated the ability of gefitinib to inhibit the interaction of TIRAP-c-Jun with in vitro experiments and with a mouse model of sepsis. Importantly, pre-treatment with gefitinib increased the survival of the mice that received a lethal dose of LPS compared to that of the controls. These findings verify the ability of gefitinib to directly disrupt the interaction of TIRAP and c-Jun, thereby inhibiting a major inflammatory response that is often observed in patients experiencing sepsis. |
| Databáze: | OpenAIRE |
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