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

The structure-activity relationship of 18-carbon fatty acids (C₁₈ 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 μM 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: C₁₈:1 . C₁₈:2 . C₁₈:3 . C₁₈:4. 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 C₁₈ UFA structure are critical to providing the potent anti-inflammatory properties in human neutrophils.