TY - JOUR
T1 - Bioactive products generated by Group V sPLA2 hydrolysis of LDL activate macrophages to secrete pro-inflammatory cytokines
AU - Boyanovsky, Boris B.
AU - Li, Xia
AU - Shridas, Preetha
AU - Sunkara, Manjula
AU - Morris, Andrew J.
AU - Webb, Nancy R.
PY - 2010/4
Y1 - 2010/4
N2 - Objective: Previous studies have established that hydrolysis of LDL by Group V secretory phospholipase A2 (GV sPLA2) generates a modified particle capable of inducing macrophage foam cell formation. The aim of the present study was to determine whether GV sPLA2-hydrolyzed LDL (GV-LDL) produces pro-atherogenic effects in macrophages independent of cholesterol accumulation. Methods and results: J-774 cells incubated with GV-LDL produced more TNF-α and IL-6 compared to cells incubated with control-LDL. Indirect immunofluorescence showed that GV-LDL but not control-LDL induced nuclear translocation of NFκB. Inhibitors of NFκB activation, effectively blocked cytokine production induced by GV-LDL. Control-LDL and GV-LDL were separated from albumin present in reaction mixtures by ultracentrifugation. The albumin fraction derived from GV-LDL contained 80% of the FFA generated and was more potent than the re-isolated GV-LDL in inducing pro-inflammatory cytokine secretion. Linoleic acid (18:2) and oleic acid (18:1) were the most abundant FFAs generated, whereas newly formed lyso-PCs contained 14:0 (myristic), 16:1 (palmitic), and 18:2 fatty acyl groups. Experiments with synthetic FFA showed that 18:1 induced J-774 cells to secrete TNF-α and IL-6. Conclusions: These results indicate that in addition to promoting atherosclerotic lipid accumulation in macrophages, GV sPLA2 hydrolysis of LDL leads to activation of NFκB, a key regulator of inflammation.
AB - Objective: Previous studies have established that hydrolysis of LDL by Group V secretory phospholipase A2 (GV sPLA2) generates a modified particle capable of inducing macrophage foam cell formation. The aim of the present study was to determine whether GV sPLA2-hydrolyzed LDL (GV-LDL) produces pro-atherogenic effects in macrophages independent of cholesterol accumulation. Methods and results: J-774 cells incubated with GV-LDL produced more TNF-α and IL-6 compared to cells incubated with control-LDL. Indirect immunofluorescence showed that GV-LDL but not control-LDL induced nuclear translocation of NFκB. Inhibitors of NFκB activation, effectively blocked cytokine production induced by GV-LDL. Control-LDL and GV-LDL were separated from albumin present in reaction mixtures by ultracentrifugation. The albumin fraction derived from GV-LDL contained 80% of the FFA generated and was more potent than the re-isolated GV-LDL in inducing pro-inflammatory cytokine secretion. Linoleic acid (18:2) and oleic acid (18:1) were the most abundant FFAs generated, whereas newly formed lyso-PCs contained 14:0 (myristic), 16:1 (palmitic), and 18:2 fatty acyl groups. Experiments with synthetic FFA showed that 18:1 induced J-774 cells to secrete TNF-α and IL-6. Conclusions: These results indicate that in addition to promoting atherosclerotic lipid accumulation in macrophages, GV sPLA2 hydrolysis of LDL leads to activation of NFκB, a key regulator of inflammation.
KW - Atherosclerosis
KW - Inflammation
KW - Lipoprotein modification
KW - NFκB
KW - Tumor necrosis factor-alpha
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U2 - 10.1016/j.cyto.2009.12.009
DO - 10.1016/j.cyto.2009.12.009
M3 - Article
C2 - 20138782
AN - SCOPUS:77049088900
VL - 50
SP - 50
EP - 57
IS - 1
ER -