Histamine regulates placental cytokine expression--in vivo study on HDC knockout mice.

Successful pregnancy is closely related to polarization toward a Th2 type immune response. As histamine is known to initiate Th2 dominance during inflammatory processes we raised the question whether histamine has any effect on the actual tuning of proper cytokine balance for the proceeding of the gestation. Histamine has multiple functions in the process of pregnancy, different studies have shown the direct and/or indirect presence of histamine action in the placenta as well. As HDC is the unique histamine producing enzyme in eukaryotes, we used HDC (so endogenous histamine)-deficient knockout mice as reliable model for studying histamine-related processes in vivo. We examined the placental histamine content and the expression of histamine receptors and Th1/Th2/Th3 type cytokines in the placenta. We showed for the first time the influence of histamine on the orchestrated regulation of placental cytokine expression. In the absence of local histamine the cytokine balance is shifted toward Th1 types at the maternal-placental interface, threatening pregnancy. We also measured splenic lymphocyte subpopulation ratios in pregnant and non-pregnant mice and found that in pregnancy they are independent of the presence of histamine.

Pyrethroid insecticides influence the signal transduction in T helper lymphocytes from atopic and nonatopic subjects.

OBJECTIVE AND DESIGN: Pyrethroids are claimed to have a low human toxicity with some neuro- and immunotoxicity. The objective of this study was to investigate the immunotoxicological properties of six commercially used pyrethroids, including natural pyrethrum and synergist piperonyl-butoxide (PBO). MATERIAL AND METHODS: PHA-stimulated cultures of T-helper lymphocytes and blood basophil incubates from nonatopic and atopic patients (IgE > 1000 IU) provided cytokine and histamine determination. Western blot analysis was used for the measurement of Th2-specific signal transducer and activator of transcription-6 (STAT6). Pyrethroids and xenobiotics were added 4 h post-plating. RESULTS: We demonstrated that interferon-gamma (IFN-gamma) production and expression was correlated with lymphocyte proliferation, however, interleukin-4 (IL-4) was down-regulated at the end of the 3 day culture. Atopics showed significantly higher IL-4 activity than nonatopics. Pyrethroids inhibited IFN-gamma and IL-4 in both groups at around 10(-5) M. Only fenvalerate and S-bioallethrin combined with 10-fold PBO in the atopic-enriched blood basophil incubates caused a weak but significant increase in histamine release. Histamine acted bidirectionally on STAT6, but pyrethroids inhibited the intracellular Th2-specific STAT6 more effectively in atopics than in nonatopics. CONCLUSION: It can be suggested that pyrethroids inhibit signal transduction in human lymphocytes ex vivo, and do not act via lymphocyte-influencing histamine release.

Pyrethroids and piperonyl-butoxide affect human T-lymphocytes in vitro.

Synthetic pyrethroids are increasingly used as insecticides and are claimed to have a relatively low human toxicity. The aim of this study was to examine the in vitro effects of the synthetic pyrethroid S-bioallethrin alone and in combination with the common synergist piperonyl-butoxide (PBO) on human blood lymphocytes and basophils in atopic individuals and non-atopic control subjects. S-bioallethrin and PBO also caused inhibition of lymphocyte proliferation (MTT-test) after a 72-h culture period in a concentration dependent manner. In contrast to the MTT-measurements the combined agents are more effective in inhibiting interleukin-4 (IL-4)- and interferon-gamma (IFN-gamma)-production. The regulatory IL-4/IFN-gamma balance showed a significant difference between atopic and non-atopic subjects after a culture period of 24-48 h in the presence of micromolar S-bioallethrin (P < 0.001). Furthermore S-bioallethrin, PBO and the combined agents induced histamine release from human basophils. Although this effect was little compared to histamine liberators like FMLP and anti-IgE, the response to S-bioallethrin and PBO was significantly different in atopic donors compared with non-atopics (P < 0.01). In scratch test experiments 4 of 18 tested atopic volunteers showed positive reaction (wheals and flares) to S-bioallethrin and permethrin, whereas no reaction could be measured in the control group (age-matched). These findings demonstrate the immuno- and allergo-toxicological properties of the synthetic pyrethroid S-bioallethrin combined with the synergistic PBO using this in vitro approach with human lymphocytes and basophils.

Effects of somatostatin on ethanol-induced gastric erosions in the rat: role of mast cells.

Somatostatin (S) inhibits hemorrhagic gastric erosions produced by ethanol. In this study we compared the dose-dependent effects of linear (reduced) and cyclic (oxidized) S with respect to mast cell degranulation. The gastric mucosal injuries were more inhibited by linear S than by cyclic S. But linear S aggravated injury at a certain dose (10(-7) mol/rat). Mucosal mast cell degranulation correlated significantly with the area of hemorrhagic mucosal lesions (r = 0.91). Both cytoprotection as well as aggravation potency of S may be connected to gastric mucosal mast cell activity in the rat.

Excretion of sulfobromophthalein in rats with iodomethane-induced depletion of hepatic glutathione.

Male urethane-anesthetized Wistar rats with biliary fistulas were infused for 60 min i.v. with sulfobromophthalein (BSP) or BSP-glutathione conjugate (BSP-GSH) at 594 nmol/100 g/min. Thirty minutes prior to the start of the infusion, 20 mg/kg iodomethane, dissolved in oliver oil, was given into the duodenum. The control received oil only. At the start of the infusion the hepatic concentration of GSH was 0.96 +/- 0.23 mg/g liver in the iodomethane-treated animals versus 1.93 +/- 0.13 mg/g liver in the control (P less than 0.001). When unconjugated BSP was infused, the excretion of total BSP (unconjugated plus conjugated) was markedly lower in the iodomethane-treated group than in the control. This difference was due solely to differences in biliary appearing conjugated BSP; the excretion of unconjugated BSP was identical in both groups. The different excretion patterns were paralleled by equal hepatic accumulation of total BSP in both groups. The ratio of unconjugated BSP/BSP-GSH in the liver was about twice as high after pretreatment with iodomethane than in the control group. When BSP-GSH instead of BSP was infused, the excretion rates of this dye were identical in both groups. The maximal transport capacity (Tm) was double that observed with infusion of unconjugated BSP in control animals. There is indirect evidence that BSP and BSP-GSH might have different excretion pathways.