Myeloid-Specific Deficiency of Long-Chain Acyl CoA Synthetase 4 Reduces Inflammation by Remodeling Phospholipids and Reducing Production of Arachidonic Acid-Derived Proinflammatory Lipid Mediators.

In response to infection or tissue damage, resident peritoneal macrophages (rpMACs) produce inflammatory lipid mediators from the polyunsaturated fatty acid (PUFA), arachidonic acid (AA). Long-chain acyl-CoA synthetase 4 (ACSL4) catalyzes the covalent addition of a CoA moiety to fatty acids, with a strong preference for AA and other PUFAs containing three or more double bonds. PUFA-CoA can be incorporated into phospholipids, which is the source of PUFA for lipid mediator synthesis. In this study, we demonstrated that deficiency of Acsl4 in mouse rpMACs resulted in a significant reduction of AA incorporated into all phospholipid classes and a reciprocal increase in incorporation of oleic acid and linoleic acid. After stimulation with opsonized zymosan (opZym), a diverse array of AA-derived lipid mediators, including leukotrienes, PGs, hydroxyeicosatetraenoic acids, and lipoxins, were produced and were significantly reduced in Acsl4-deficient rpMACs. The Acsl4-deficient rpMACs stimulated with opZym also demonstrated an acute reduction in mRNA expression of the inflammatory cytokines, Il6, Ccl2, Nos2, and Ccl5 When Acsl4-deficient rpMACs were incubated in vitro with the TLR4 agonist, LPS, the levels of leukotriene B4 and PGE2 were also significantly decreased. In LPS-induced peritonitis, mice with myeloid-specific Acsl4 deficiency had a significant reduction in leukotriene B4 and PGE2 levels in peritoneal exudates, which was coupled with reduced infiltration of neutrophils in the peritoneal cavity as compared with wild-type mice. Our data demonstrate that chronic deficiency of Acsl4 in rpMACs reduces the incorporation of AA into phospholipids, which reduces lipid mediator synthesis and inflammation.

[Immunomodulatory properties of therapeutic and subtherapeutic levels of theophylline: effect on metabolic activity of human monocytes]. / Immunomodulacyjne wlasciwosci terapeutycznych i subterapeutycznych stezen teofiliny: wplyw na aktywnosc metaboliczna monocytów ludzkich.

The aim of present study was to analyze the potential immunomodulatory effects of theophylline. We studied the influence of therapeutic and subtherapeutic drug concentrations on the metabolic human monocytes activity using the chemiluminescence test, that allows to evaluate the production of free oxygen radicals. Subtherapeutic theophylline concentrations of 2.5 and 5 micrograms/ml significantly increased monocytes spontaneous chemiluminescence activity. Moreover, in concentrations 5-20 micrograms/ml theophylline interfered with the process of monocyte activation by zymosan: decreasing O2-total and maximal production as well as affecting duration of the "respiratory burst" reaction. Correlation between theophylline concentration and intensity of its suppressive effect was also observed. Therefore we concluded that theophylline might be useful in the treatment of allergic inflammation characterising bronchial asthma.

Studies on human milk macrophages: effect of activation on phagocytosis and secretion of prostaglandin E2 and lysozyme.

Breast milk macrophages cultured in vitro synthesized and secreted increasing amounts of protein, lysozyme, and prostaglandin E2(PGE2) into the extracellular medium. These cells were also shown to actively phagocytose labeled zymosan particles in culture. Morphologic characteristics, phagocytosis, and secretory responses of the macrophages were altered depending on the presence of various stimuli in the culture. Concanavalin A, endotoxin and zymosan particles, but not latex particles, all resulted in an increased PGE2 secretion into the medium. Although total protein synthesis was not altered by any of these stimuli, Concanavalin A and endotoxin resulted in a decreased lysozyme concentration in the extracellular medium. Concanavalin A enhanced, whereas endotoxin and prior phagocytosis of latex particles inhibited phagocytosis of labeled zymosan particles. These findings indicate that phagocytosis and secretions of milk macrophages may be altered depending on the nature of the stimulating agent.