Fig. 4.

Activation of NF-κB-dependent cytokine production through lipid peroxidation. When non-cytotoxic levels of iron-laden particles interact with macrophages, the resulting lipid peroxidation in the area of the plasma membrane with which the particle interacts, produces a stress response that activates NF-κB and pro-inflammatory cytokine production. Lipid raft disruption caused by minor lipid peroxidation, results in the release of calcium from annexin 6 leading to the activation of phosphatidylcholine specific phospholipase C (PC-PLC) activation that produces diacylglycerol (DAG). DAG then activates acidic sphingomyelinase (ASM) that produces ceramide. Ceramide then activates ceramide-activated protein kinase (CAPK), which phosphorylates IκB allowing NF-κB to migrate to the nucleus. The PC-PLC-dependent pathway can also be stimulated by endotoxin, again representing a non-physiological stress response [75], [76].