TNF/TNF-R1 pathway is involved in doxorubicin-induced acute sterile inflammation

Doxorubicin is an anthracycline antibiotic, which is used in treatment of cancer and it works by induction of apoptosis in cancerous cells. 1 In vivo , apoptotic cells are rapidly cleared preferentially by monocytes and neutrophil migration is inhibited 2 to limit tissue injury and inflammation. More recently, few anti-cancer drugs, including anthracyclines (doxorubicin) were shown to evoke apoptosis in cancerous cells, which is associated with immune system activation (i.e. immunogenic apoptosis). 3 , 4 In our previous study we reported that doxorubicin can induce acute inflammation in peritoneum, which is associated with apoptosis. 5 Doxorubicin-killed cells could be also a source of damage-associated molecular patterns (DAMPs) leading to inflammation and tumor necrosis factor (TNF) production, which would amplify the inflammatory response triggered by DAMPs. TNF is a pleiotropic cytokine that binds to receptors TNF-R1 and TNF-R2 and, depending on cell type, triggers different signaling pathways, including cell death and inflammation. 6 This study aimed to examine whether TNF contributes to the doxorubicin-induced acute sterile inflammation.