Butyrylcholinesterase activity and lymphocyte subpopulations in peripheral blood of Kuwaiti women experiencing recurrent spontaneous abortion.

This study has evaluated the hypothesis that activity of the detoxifying enzyme butyrylcholinesterase (BuChE) correlates with levels of serum anti-cardiolipin antibodies (ACA) and T lymphocytes in peripheral blood of women experiencing recurrent spontaneous abortion (RSA). Peripheral venous blood from 16 non-pregnant, RSA-afflicted women and 8 healthy non-pregnant women was analyzed for frequency of T lymphocyte subpopulations by two-color flow cytometry and for serum BuChE using butyrylthiocholine iodide/spectrophotometry. RSA-afflicted women with high serum ACA, but not those with normal ACA levels, exhibited significantly increased percentages of CD4+CD25+ cells (p<0.01) and CD4+HLA-DR+ cells (p<0.05) relative to healthy women. CD4+CD25+(high) cells were significantly lower (p<0.05), while CD4+CD25+(low) cells were significantly higher (p<0.01), in women with elevated ACA compared to healthy women and to RSA women with normal ACA. Relative to healthy, non-pregnant subjects, serum BuChE activity in RSA patients was elevated, both for those with normal ACA (p<0.001) and elevated ACA levels (p<0.01). Among healthy controls, a significant positive correlation was observed between frequency of CD3+NK cells and BuChE activity (p<0.01), but not for RSA-afflicted subjects. A positive correlation between BuChE activity and frequency of CD4+CD25+ cells, as well as CD4+CD25+(high) cells, was observed in the RSA-afflicted subject group with elevated ACA (p<0.05), which may be related to induction of BuChE by toxic metabolites resulting from pathogenic T cell activity. It is concluded that, among RSA patients, high serum ACA correlates with elevated levels of activated T cells and reduced CD4+CD25+(high)/CD4+CD25+(low) cells in comparison to healthy women or those afflicted with RSA but with normal ACA. BuChE activity is observed to be elevated in RSA patients irrespective of serum ACA status.

Cytokines and cytokine inducers stimulate prostaglandin E2 entry into the brain.

Cytokine inducers and cytokines increase the circulating level of prostaglandin E2 (PGE2) during the acute-phase immune response. This occurs simultaneously with the onset of fever, indicating that brain levels of PGE2 also increase. This raises the possibility that PGE2 produced in the peripheral circulation, not necessarily at distant sites from the brain, may penetrate the brain and be present in the cerebrospinal fluid (CSF). Blood and CSF levels of PGE2 in rabbits were measured by radioimmunoassay during fever stimulated in response to lipopolysaccharide (LPS), polyinosinic:polycytidylic acid (poly I:C) and interleukin-1 (IL-1) given i.v. The effect of the prostaglandin synthesis inhibitor ketoprofen on these parameters was also studied. In addition, the level of radioactivity in the CSF was measured following the administration of [125I]-labelled PGE2 i.v. during fever induced by LPS, poly I:C, IL-1 or tumor necrosis factor alpha (TNFalpha). Both LPS and poly I:C stimulated an increase in plasma and CSF levels of PGE2 over a 5-h period with a peak at 60 min and 90 min, respectively, which occurred in parallel with the changes in body temperature. Ketoprofen abolished the rise in plasma and CSF PGE2 levels and the rise in body temperature in response to LPS, poly I:C and IL-1. In experiments where animals were given [125I]-labelled PGE2 i.v., radioactivity well above the background level was measured in samples of CSF collected from LPS-, poly I:C-, IL-1- or TNFalpha-pretreated animals. In contrast the radioactivity present in samples of CSF perfusate collected from control (saline-treated) animals was indistinguishable from the background level. These data indicate that cytokine inducers and cytokines increase the mass level of PGE2 in blood and CSF and also increases the entry, from the peripheral circulation, of radiolabelled PGE2 into the third cerebral ventricle.

Interleukin-1 alpha (IL-1 alpha) production by alveolar macrophages in patients with acute lung diseases: the influence of zinc supplementation.

The relationship between zinc treatment and interleukin-1 alpha (IL-1 alpha) production by cultured alveolar macrophages (AM) in patients with pulmonary tuberculosis and bacterial pneumonia was investigated. AM (1 x 10(6) cells/ml) from 6 patients with pulmonary tuberculosis, 7 patients with bacterial pneumonia and 4 healthy volunteers were cultured with either two different concentrations of zinc chloride (Znl = 1 microgram/ml and Zn2 = 5 micrograms/ml) or cell culture media alone (control) for an initial period of 6 hours and then stimulated with 3 different immunomodulator agents and reincubated for a further 24 h. IL-1 alpha in culture supernatants was measured by enzyme-linked immunosorbent assay (ELISA). In the absence of Znl or Zn2 Polyinosinic:Polycytidylic acid (Poly I:C 1 microgram/ml), Lipopolysaccharide (LPS 100 ng/ml) and Tumour necrosis factor-alpha (TNF-alpha 10 ng/ml) significantly increased the production of IL-1 alpha from AM in both patients and healthy subjects (p < 0.001) compared to control (media only). Zn1 and Zn2 significantly increased the production of IL-1 alpha (p < 0.001) in culture supernatants in the absence of either Poly I:C, LPS or TNF-alpha in patients but not in healthy group. In contrast, the presence of LPS or TNF-alpha significantly reduced Zn1 or Zn2-stimulated release of IL-1 alpha from AM in patients and healthy subjects (p < 0.01). However, Poly I:C decreased only Zn1-stimulated release of IL-1 alpha. These results suggest that zinc can regulate the production of IL-1 alpha from AM in patients with pulmonary tuberculosis or bacterial pneumonia.

Pyrogenic immunomodulators increase the level of prostaglandin E2 in the blood simultaneously with the onset of fever.

Blood prostaglandin E2 (PGE2) levels, estimated by radioimmunoassay, and body temperatures of conscious rabbits were measured simultaneously during fever in response to polyinosinic: polycytidylic acid, lipopolysaccharide and interleukin 1/endogenous pyrogen. The effects of the antipyretic agent ketoprofen on both parameters was also studied. Significant rises (in the order of 6- to 8-fold) in the PGE2 level were observed after injection of either of the three pyrogens and occurred simultaneously with the rise in temperature. Ketoprofen given after the onset of fever in response to the pyrogens produced an immediate defervescence and a simultaneous decrease in plasma PGE2. Ketoprofen given before the pyrogens prevented any rise in either body temperature or plasma PGE2 level. When animals were subjected to an environmental temperature of 34 degrees C a hyperthermia was observed without any change in the blood PGE2 level. These results suggest that an increase in the blood PGE2 level may contribute to the pathogenesis of fever.

The pyrogenic actions of the interferon-inducer, polyinosinic:polycytidylic acid are antagonised by ketoprofen.

The effect of various doses of polyinosinic:polycytidilic acid (Poly I:C) in the range (0.25-250 micrograms/kg) administered i.v. on the body temperature of rabbits was investigated. The effect of ketoprofen on the febrile responses was also studied. The threshold dose of Poly I:C administered which produced a fever was between 0.25 and 0.5 micrograms/kg and a double-sigmoidal dose-response relationship was observed. A sigmoidal relationship was obtained with lower doses from 0.25 micrograms/kg to an apparent maximum with 2.5 micrograms/kg and another with higher doses from 5 micrograms/kg to another apparent maximum with 250 micrograms/kg. Ketoprofen (3 mg/kg) given s.c. 15 min prior to Poly I:C inhibited the production of fever. Ketoprofen administered after the onset of fever resulted in an immediate deffervescence. These results suggest that febrile responses to Poly I:C involve prostaglandin biosynthesis.