In vitro effect of cetirizine on PGE2 release by rat peritoneal macrophages and human monocytes.

Cetirizine was first described as a specific anti-H1 molecule displaying potent antiallergic activity. It was later found that its pharmacological properties extended to cellular actions as on eosinophil recruitment at inflammatory sites in allergic patients. Monocytes and macrophages participate in allergic mechanisms, particularly through high affinity H1 and H2 membrane receptors and generation of pro- and anti-inflammatory agents; among them histamine-induced factors, IL-1 and prostanoids are of importance. The aim of this work was to investigate the effect exerted by various concentrations of cetirizine (0.1-10 micrograms/ml) applied in vitro to human monocytes and peritoneal rat macrophages cultured for 24 h. Peritoneal macrophages were collected either from normal or experimentally inflamed rats. Human monocytes, isolated from peripheral blood, were studied either in a resting state or after stimulation by LPS from Escherichia coli (1 and 10 micrograms/ml). Cetirizine (10 micrograms/ml) significantly enhanced IL-1 release by human monocytes stimulated by a weak LPS concentration (1 microgram/ml) but could not modify the maximal increase of IL-1 release induced by 10 micrograms/ml of LPS. It did not exert any effect on resting cells. Cetirizine (0.1-10 micrograms/ml) enhanced PGE2 release by resting human monocytes. Concentrations of 1 and 10 micrograms/ml enhanced PGE2 release by LPS-stimulated monocytes, and by healthy and inflamed rat macrophages. This effect was concentration-dependent. Our findings point to an anti-inflammatory action of cetirizine via PGE2 release and histamine H2 interactions. Cetirizine did not directly modify IL-1 generation by resting monocytes but the IL-1 production observed after LPS stimulation could promote the mechanisms by which PGE2 is released.

The immunomodulating agent RU 41740 complexed with very-low-density lipoproteins enhances human polymorphonuclear neutrophil oxidative metabolism in vitro.

Added to human serum in vitro, RU 41740, an immunomodulating agent extracted from Klebsiella pneumoniae, binds selectively to lipoproteins containing apolipoprotein B (low-density lipoproteins and very-low-density lipoproteins, VLDL) and, at higher concentrations, to lipoproteins containing apolipoprotein A (high-density lipoproteins). The fact that lipoproteins modulate polymorphonuclear neutrophil (PMN) functions led us to suspect that the VLDL-RU 41740 complex might affect PMN functions. In this study, the effect of this complex on PMN superoxide generation was measured in the presence and absence of the classical stimulants formyl-methionyl-leucyl-phenylalanine and phorbol myristate acetate. The VLDL-RU 41740 complex enhanced the stimulating effect of VLDL on quiescent PMN, but not following stimulation with formyl-methionyl-leucyl-phenylalanine. In contrast, it partially counteracted the inhibiting effect exerted by VLDL alone on phorbol myristate acetate stimulation. Such a complex might be formed in vivo during RU 41740 therapy and constitute an important feature in the immunostimulating properties of the drug.

In vitro modulating effect of human very-low-density lipoproteins on human polymorphonuclear leukocyte oxidative metabolism and migration.

In this work, the in vitro effects of very-low-density lipoproteins (VLDL) on human polymorphonuclear leukocyte (PMN) oxidative metabolism and migration were studied. VLDL stimulated PMN superoxide generation in absence of other stimulating agents. The effect of VLDL from normotriglyceridemic subjects was more marked than with VLDL from hypertriglyceridemic subjects. VLDL reduced in a dose-dependent manner the luminol-dependent chemiluminescence of PMN stimulated by phorbol myristate acetate (PMA) and, to a lesser degree, by opsonized zymosan. This effect was observed with VLDL concentrations found in healthy and hypertriglyceridemic patients. Superoxide anion generation was also reduced by preincubation of PMN with VLDL before stimulation with PMA but not opsonized zymosan. VLDL were not cytotoxic for PMN. The above effects appear to be an intrinsic property of VLDL and might lead to reduced PMN-mediated non-specific host defences in hypertriglyceridemic subjects.