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Journal of Lipid Research, Vol. 50, 1395-1408, July 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

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

Tsong-Long Hwang^1,*, Yi-Chia Su^*, Han-Lin Chang^*, Yann-Lii Leu^*, Pei-Jen Chung^*, Liang-Mou Kuo and Yi-Ju Chang^*

^* Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, Taiwan
Department of General Surgery, Chang Gung Memorial Hospital at Chia-Yi, Taiwan

This work was supported by grants from the Chang Gung Medical Research Foundation and the National Science Council, Taiwan. The authors disclose that there is no conflict of interest.

Published, JLR Papers in Press, March 17, 2009.

¹ To whom correspondence should be addressed. e-mail: htl{at}mail.cgu.edu.tw

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.

Supplementary key words calcium • cAMP • structure-activity relationship • plasma membrane Ca²⁺-ATPase

Abbreviations: Ba²⁺, barium; C18, 18-carbon; CB, cytochalasin B; CVA, cis-vaccenic acid; ER, endoplasmic reticulum; ERCA, endoplasmic reticulum Ca²⁺-ATPase; FMLP, formyl-L-methionyl-L-leucyl-L-phenylalanine; IC₅₀, 50% inhibitory concentration; IP₃, 1,4,5-triphosphate; LDH, lactate dehydrogenase; LA, linoleic acid; LA, -linoleic acid; LA, -linoleic acid; NCX, Na⁺-Ca²⁺ exchanger; OA, oleic acid; O₂^•–, superoxide anion; PDE, phosphodiesterase; PKC, protein kinase C; PMA, phorbol myristate acetate; PMCA, plasma membrane Ca²⁺-ATPase; ROS, reactive oxygen species; SA, stearic acid; SOCE, store-operated Ca²⁺ entry; SOD, superoxide dismutase; UFA, unsaturated fatty acid

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