Metabolic stress occurs frequently in tumors and in normal tissues undergoing transient ischemia. Nutrient deprivation triggers, among many potential cell death-inducing pathways, an endoplasmic reticulum (ER) stress response with the induction of the integrated stress response transcription factor ATF4. However, how this results in cell death remains unknown. Here we show that glucose deprivation triggered ER stress and induced the unfolded protein response transcription factors ATF4 and CHOP. This was associated with the nontranscriptional accumulation of TRAIL receptor 1 (TRAIL-R1) (DR4) and with the ATF4-mediated, CHOP-independent induction of TRAIL-R2 (DR5), suggesting that cell death in this context may involve death receptor signaling. Consistent with this, the ablation of TRAIL-R1, TRAIL-R2, FADD, Bid, and caspase-8 attenuated cell death, although the downregulation of TRAIL did not, suggesting ligand-independent activation of TRAIL receptors. These data indicate that stress triggered by glucose deprivation promotes the ATF4-dependent upregulation of TRAIL-R2/DR5 and TRAIL receptor-mediated cell death.

Highlights d Chemotherapeutic drugs, taxol and taxotere, can promote inflammation d Taxanes promote an ER stress response leading to upregulation of TRAIL receptors d ER-stress-induced DR5/TRAIL-R2 activation promotes inflammatory cytokine production d TRAIL receptors act as sensors of ER perturbation, leading to death or inflammation

This chapter discusses the important roles of iron and zinc in inflammation, describing related molecular pathways and mediators. Their relevant interactions with chronic health conditions, such as obesity, atherosclerosis and diabetes, are also discussed.