Suppression of superoxide anion and elastase release by C18 unsaturated fatty acids in human neutrophils

The structure-activity relationship of 18-carbon fatty acids (C-18 FAs) on human neutrophil functions and their underlying mechanism were investigated. C18 unsaturated (U) FAs potently inhibited superoxide anion production, elastase release, and Ca2+ mobilization at concentrations of <10 mu M in formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP)-activated human neutrophils. However, neither saturated FA nor esterified UFAs inhibited these neutrophil functions. The inhibitory potencies of C18 UFAs decreased in the following order: C-18: 1 > C-18: 2 > C-18: 3 > C-18: 4. Notably, the potency of attenuating Ca2+ mobilization was closely correlated with decreasing cellular responses. The inhibitions of Ca2+ mobilization by C18 UFAs were not altered in a Ca2+-containing Na+-deprived medium. Significantly, C18 UFAs increased the activities of plasma membrane Ca2+-ATPase (PMCA) in neutrophils and isolated cell membranes. In contrast, C18 UFAs failed to alter either the cAMP level or phosphodiesterase activity. Moreover, C18 UFAs did not reduce extracellular Ba2+ entry in FMLP-and thapsigargin-activated neutrophils. In summary, the inhibition of neutrophil functions by C18 UFAs is attributed to the blockade of Ca2+ mobilization through modulation of PMCA. We also suggest that both the free carboxy group and the number of double bonds of the C-18 UFA structure are critical to providing the potent anti-inflammatory properties in human neutrophils.-Hwang, T-L., Y-C. Su, H-L. Chang, Y-L. Leu, P-J. Chung, L-M. Kuo, and Y-J. Chang. Suppression of superoxide anion and elastase release by C18 unsaturated fatty acids in human neutrophils. J. Lipid Res. 2009. 50: 1395-1408.