Induction and modulation of apoptosis in neonatal monocytes by polyunsaturated fatty acids

Polyunsaturated fatty acids (PUFAs), known modulators of the immune response, are the Apoptosis; source of essential fatty acids in total parenteral nutrition - dependent patients. Critically ill infants on Human; TPN have an increased incidence of sepsis, and lipid emulsions depress various immune functions. Lipid mediators; Recent studies have demonstrated that PUFAs induce apoptosis in various tissue cells in vitro and ex Inflammation; vivo. The susceptibility of neonatal monocytes, as major early effector cells in the host response to Fatty acids sepsis, to PUFA-mediated apoptosis and the mechanisms associated with PUFA-induced apoptosis were investigated. Both n-3 and n-6 PUFAs induced rapid, dose-dependent cell death in purified monocytes. Polyunsaturated fatty acids induced significant activation of upstream caspases 8 and 9 as well as caspase 3. The PUFA treatment resulted in a 4-fold increase in oxidative stress and a loss of monocyte mitochondrial potential compared with carrier controls (P < .05). The addition of cyclosporin, which blocks the development of mitochondrial transition pores, completely abolished the proapoptotic effects of PUFAs. Although Trolox (Sigma Aldrich) reduced PUFA-induced intracellular oxidative stress in neonatal monocytes, apoptosis was not blocked by this potent antioxidant. The data identify PUFAs as potent inducers of monocyte apoptosis, which can occur independently of the induction of oxidative stress, by using a mitochondrial dependent pathway. The TPN-dependent infant may be particularly sensitive to such PUFA effects, having a relatively poor capacity to both use and clear PUFAs. (C) 2007 Elsevier Inc. All rights reserved.