Docosahexaenoic acid, a constituent of rodent fetal serum and fish oil diets, inhibits acquisition of macrophage tumoricidal function

Lynn B. Dustin, Colleen M. Shea, Roy J. Soberman, Christopher Y. Lu

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Abstract

Macrophage (Mφ) activation is deficient in the fetus and neonate, at times when the serum concentration of docosahexaenoic acid (DHA; 22:6n3) is approximately 10-fold higher than in the adult. We tested the effects of highly purified DHA on Mφ activation in vitro. Mφ were stimulated with rIFN-γ plus either of two second or 'triggering' signals, LPS or heat-killed Listeria monocytogenes. Mφ activation was assayed as the lysis of P815 mastocytoma cells, which are resistant to TNF-α. DHA inhibited the activation of peritoneal Mφ and the Mφ line RAW264.7 in a dose-dependent manner at concentrations between 20 and 160 μM. These concentrations are found in fetal and neonatal rodent sera. Another polyunsaturated fatty acid, arachidonic acid (20:4n6), was much less inhibitory. In contrast to its profound effect on tumoricidal activation, DHA did not inhibit phagocytosis and catabolism of 125I-heat-killed Listeria monocytogenes. Increasing the rIFN-γ or second signals reduced the inhibition of tumoricidal activation by DHA but not Mφ incorporation of 14C-DHA. When the rIFN-γ and second signals were separated in time, DHA was far more inhibitory if delivered with the triggering signal than if delivered with the rIFN-γ. However, the incorporation of 14C-DHA was the same under these two conditions. In Mφ treated with DHA during LPS stimulation, the inhibition was time-dependent, requiring more than 2 h. Although DHA inhibits cyclooxygenase activity, its inhibition of Mφ activation was not reversed with the following cyclooxygenase products: PGE2, a stable TXA2 analog (U-46, 619) or a stable PGI2 analog (Iloprost). Although DHA is metabolized by lipoxygenases, the inhibition was not reversed by the lipoxygenase inhibitors 5, 8, 11, 14-eicosatetraynoic acid and nordihydroguaiaretic acid. Altogether, the data indicate that DHA, at concentrations present in fetal and neonatal sera, inhibits Mφ activation and may contribute to the previously observed deficits in Mφ function in the fetus and neonate.

Original languageEnglish (US)
Pages (from-to)4888-4897
Number of pages10
JournalJournal of Immunology
Volume144
Issue number12
StatePublished - Jan 1 1990

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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