title: Docosahexaenoic acid, a constituent of rodent fetal serum and fish oil diets, inhibits acquisition of macrophage tumoricidal function.
abstract: Macrophage (M phi) 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 M phi activation in vitro. M phi were stimulated with rIFN-gamma plus either of two second or "triggering" signals, LPS or heat-killed Listeria monocytogenes. M phi activation was assayed as the lysis of P815 mastocytoma cells, which are resistant to TNF-alpha. DNA inhibited the activation of peritoneal M phi and the M phi line RAW264.7 in a dose-dependent manner at concentrations between 20 and 160 microM. 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-gamma or second signals reduced the inhibition of tumoricidal activation by DHA but not M phi incorporation of 14C-DHA. When the rIFN-gamma and second signals were separated in time, DHA was far more inhibitory if delivered with the triggering signal than if delivered with the rIFN-gamma. However, the incorporation of 14C-DHA was the same under these two conditions. In M phi treated with DHA during LPS stimulation, the inhibition was time-dependent, requiring more than 2 h. Although DHA inhibits cyclooxygenase activity, its inhibition of M phi 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 M phi activation and may contribute to the previously observed deficits in M phi function in the fetus and neonate.
authors: Committee on Immunology, Harvard Medical School, Boston, MA 02115.
authors: L B
authors: LB
authors: Dustin
authors: C M
authors: CM
authors: Shea
authors: R J
authors: RJ
authors: Soberman
authors: C Y
authors: CY
authors: Lu
mesh_terms: D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D005395:Fish Oils; D007111:Immunity, Cellular / Q000187:drug effects*; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000494:pharmacology; D008084:Lipoxygenase / Q000378:metabolism; D008089:Listeria monocytogenes / Q000276:immunology; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects*; D010529:Peritoneal Cavity / Q000166:cytology; D010587:Phagocytosis / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011994:Recombinant Proteins
chemical_list: D005395:Fish Oils; D011994:Recombinant Proteins; D004281:Docosahexaenoic Acids; D007371:Interferon-gamma; D008084:Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases