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Inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A reductase, commonly referred to as statins, are inhibitors of cholesterol biosynthesis. They are broadly used for treating hypercholesterolemia and for prevention of cardio-and cerebrovascular diseases. Recent publications show that statins also act as immunomodulatory drugs. Here, we show that lipophilic statins inhibit NK-cell degranulation and cytotoxicity. This effect was reversible by addition of substrates of isoprenylation, but not by addition of cholesterol. In NK-target cell conjugates intracellular Ca 21 flux was unaffected by statin treatment. However, statins strongly reduced the amount of conjugate formation between NK and target cells. This inhibition was paralleled by a statin-dependent inhibition of LFA-1-mediated adhesion and a reduction of NK-cell polarization. This demonstrates that statins impair the formation of effector-target cell conjugates resulting in the disruption of early signaling and the loss of NK-cell cytotoxicity.Key words: Adhesion molecules . Cytotoxicity . Human . NK cells IntroductionNK cells belong to the innate arm of the immune system and are important for an early immune response against viral infections and against tumor formation [1]. They are able to detect and selectively kill potentially dangerous cells. Furthermore, they can secrete cytokines and thereby mediate the communication between the innate and adaptive parts of an immune response. Specific killing of infected and transformed cells depends on several discrete steps that lead to polarization and exocytosis of lytic granules towards the target cell [2,3]. As a very first step the contact between NK cells and potential targets is established. Different NK-cell receptors and adhesion molecules mediate this event. LFA-1 plays a special role in the complete process of NK-cell activation. Engagement of LFA-1 by its ligand ICAM-1 on target cells is the central step in the stable adhesion of NK cells to their target cells and is sufficient to induce the polarization of lytic granules in resting NK cells [4,5]. NK-cell cytotoxicity is achieved by degranulation of these accumulated granules in the direction of the target. For this, mobilization of Ca 21 from intracellular stores is needed, which is mediated by the activation of the phospholipase C-g (PLCg) and PKC signaling pathways [6]. Inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, commonly referred to as statins, are potent inhibitors of cholesterol biosynthesis. They mimic HMGCoA and thereby block the active site of this essential enzyme [7]. Statins are broadly used as a pharmacologic therapy for treating hypercholesterolemia and for prevention of cardio-and cerebrovascular diseases [8]. Accumulating evidence occurs that statins also act as immunomodulatory drugs [9][10][11]. In various experimental settings they were shown to affect different kinds of immune cells including T cells [12,13], B cells [14] and antigenpresenting cells [13]. Also, the function of NK cells can be inh...

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Specific antisera against tetrahydroaldosterone (TH-Aldo) were raised in two white New Zealand rabbits. 3\g=a\,5\g=b\-TH-aldo-20-oxime-bovine-serum albumin complex was used as antigen. The resulting titers were 1:18 000 and 1:16 000. Except tetrahydrocortisol (THF) (0.23%) and tetrahydro\x=req-\ 18-hydroxy-11-dehydrocorticosterone (18-OH-THA) (3.2 %), all steroids and steroid metabolites gave negligible cross-reactions. Immunograms of the paper chromatograms made from the n-butanol-extract of the urines, as well as after \g=b\-glucuronidase treatment and dichlormethane extraction, were studied to further define the specificity of the antiserum. Antibody H1 (used in this study) reacted with aldosterone-18-gluc., a TH-aldosterone-glucuronide (probably the 21-glucuronide) and an unidentified less polar material. Two methods were developed: a) TH-Aldo-glucuronidc(s) estimation after ethylacetate pre-extraction as a rapid screening test of endogenous aldosterone production.b) estimation of TH-aldosterone using one chromatographic system. The results of method a) showed a significant correlation with the values obtained by technique b). Normal values (method b) were 25.88 \m=+-\16.50 \g=m\g/24h(range 9.5\p=n-\64.8 \g=m\g/24h). A significant correlation was also shown between the TH-aldo (technique b) and 18-gluc. values.TH-Aldo is the major metabolite of aldosterone isolated from human urine (Ulick 8c Liebermann 1957; Ulick 8c Vetter 1962). It is formed in the liver and excreted as glucuronide. 15-40°/o of the secreted aldosterone is excreted in the Partly presented at the

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