Inhibition of the TIRAP-c-Jun interaction as a therapeutic strategy for AP1-mediated inflammatory responses

Srivastava M., Saqib U., BANERJEE S., Wary K., Kizil B., Muthu K., ...More

INTERNATIONAL IMMUNOPHARMACOLOGY, vol.71, pp.188-197, 2019 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 71
  • Publication Date: 2019
  • Doi Number: 10.1016/j.intimp.2019.03.031
  • Journal Name: INTERNATIONAL IMMUNOPHARMACOLOGY
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.188-197
  • Keywords: Inflammation, Macrophage, Activator protein-1 (AP-1), Prointlammatory cytokines, c-Jun, TIRAP, TOLL-LIKE RECEPTORS, NUCLEAR TRANSLOCATION, ADAPTER MOLECULE, FOS, MYD88, AP-1, HETERODIMERS, ACTIVATION, SUPPRESSOR, CELLS
  • Middle East Technical University Affiliated: Yes

Abstract

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.