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

Srivastava, Mansi
Saqib, Uzma
Banerjee, Sreeparna
Wary, Kishore
Kizil, Burak
Muthu, Kannan
Baig, Mirza S.
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.