Dietary omega-3 polyunsaturated fatty acids inhibit phosphoinositide formation and chemotaxis in neutrophils.
Earlier studies demonstrated that dietary omega-3 polyunsaturated fatty acid (PUFA) supplementation attenuates the chemotactic response of neutrophils and the generation of leukotriene (LT) B4 by neutrophils stimulated with calcium ionophore; however, the mechanisms and relationship of these effects were not examined. Neutrophils and monocytes from eight healthy individuals were examined before and after 3 and 10 wk of dietary supplementation with 20 g SuperEPA daily, which provides 9.4 g eicosapentaenoic acid (EPA) and 5 g docosahexaenoic acid. The maximal neutrophil chemotactic response to LTB4, assessed in Boyden microchambers, decreased by 69% after 3 wk and by 93% after 10 wk from prediet values. The formation of [3H]inositol tris-phosphate (IP3) by [3H]inositol-labeled neutrophils stimulated by LTB4 decreased by 71% after 3 wk (0.033 +/- 0.013% [3H] release, mean +/- SEM) and by 90% after 10 wk (0.011 +/- 0.011%) from predict values (0.114 +/- 0.030%) as quantitated by beta-scintillation counting after resolution on HPLC. LTB4-stimulated neutrophil chemotaxis and IP3 formation correlated significantly (P < 0.0001); each response correlated closely and negatively with the EPA content of the neutrophil phosphatidylinositol (PI) pool (P = 0.0003 and P = 0.0005, respectively). Neither the affinities and densities of the high and low affinity LTB4 receptors on neutrophils nor LTB4-mediated diglyceride formation changed appreciably during the study. Similar results were observed in neutrophils activated with platelet-activating factor (PAF). The summed formation of LTB4 plus LTB5 was selectively inhibited in calcium ionophore-stimulated neutrophils and was also inhibited in zymosan-stimulated neutrophils. The inhibition of the summed formation of LTB4 plus LTB5 in calcium ionophore-stimulated neutrophils and in zymosan-stimulated neutrophils did not correlate significantly with the EPA content of the PI pool. The data indicate that dietary omega-3 PUFA supplementation inhibits the autoamplification of the neutrophil inflammatory response by decreasing LTB4 formation through the inactivation of the LTA epoxide hydrolase and independently by inhibiting LTB4- (and PAF) stimulated chemotaxis by attenuating the formation of IP3 by the PI-selective phospholipase C. This is the initial demonstration that dietary omega-3 PUFA supplementation can suppress signal transduction at the level of the PI-specific phospholipase C in humans.
Department of Medicine, Harvard Medical School, Boston, MA 02115.
R I
RI
Sperling
A I
AI
Benincaso
C T
CT
Knoell
J K
JK
Larkin
K F
KF
Austen
D R
DR
Robinson
D000328:Adult; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003864:Depression, Chemical; D004042:Dietary Fats, Unsaturated / Q000494:pharmacology*; D004075:Diglycerides / Q000096:biosynthesis; D005227:Fatty Acids / Q000032:analysis; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D007975:Leukotriene B4 / Q000096:biosynthesis / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D010716:Phosphatidylinositols / Q000096:biosynthesis*; D010972:Platelet Activating Factor / Q000494:pharmacology
D004042:Dietary Fats, Unsaturated; D004075:Diglycerides; D005227:Fatty Acids; D015525:Fatty Acids, Omega-3; D006893:Hydroxyeicosatetraenoic Acids; D010716:Phosphatidylinositols; D010972:Platelet Activating Factor; D007975:Leukotriene B4; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid