Band 13, Heft 1

The value of urinary neopterin as a predictive marker for disease progression in SIV- and HIV-2-infected rhesus (Macaca mulatta) and cynomolgus macaques (Macaca fascicularis) was assessed by comparing pre- with postinfection data. Before infection stable baselines for neopterin were observed in both species with significantly higher concentrations in cynomolgus macaques than in rhesus macaques. After infection of cynomolgus macaques with human immunodeficiency virus type 2 (HIV-2) neopterin concentrations exceeded 1.2 - 4.2 times preinfection values, whereas rhesus monkeys infected with simian immunodeficiency virus (SIV) yielded concentrations of more than 8 times above baseline. Increased neopterin concentrations always preceded seroconversion. No rise of neopterin was observed in cynomolgus macaques remaining seronegative after inoculation with HIV-2, whereas after inoculation with SIV neopterin was slightly elevated in rhesus monkeys despite remaining seronegative. In animals with high virus replication a pronounced increase of neopterin levels was followed by signs of immunodeficiency. Therefore like in HIV-1-infected man, in macaques infected with SIV or HIV-2 the urinary neopterin concentration is an early and reliably predictive marker for AIDS disease progression and reflects pathogenicity. This parameter can be easily assessed in study protocols for drug and vaccine tests in monkeys as in man.

It is well established now that in diseases with activated cell-mediated immunity increased formation of neopterin and degradation of tryptophan is an indication of endogenous production of interferon-γ in patients. Therefore increased neopterin levels are associated with increased kynuremne levels and decreased tryptophan in patients suffering from virus infections, malignant diseases or autoimmunity. To investigate cell-mediated immunity m schizophrenia, neopterin, L-kynurenine, L-tryptophan and T-cell-subsets were measured in 10 chronic schizophrenic patients, addmitted to hospital due to acute psychiatric relapse. Low neopterin concentrations were found at the beginning of hospitalisation and followed by a significant increase at the time of discharge (p = 0.02). Mean neopterin values were still within the 95 th percentile of healthy controls. Kynuremne levels showed a similar development (p = 0.03) as neopterin whereas tryptophan values were low at admission without any significant changes thereafter. CD3 + and CD4+-cells presented with highest numbers at admission, followed by a continuous decrease and NK-cells were found lowest on day 0 with a gradual increase by day 7. These findings argue against acute virus infection in acutely ill schizophrenic patients because this would be associated with incerased neopterin fromation and tryptophan dagradation, rather the data would be in line with a shift from TH-1 to TH-2-type immune reaction which which is common in chronic infections.

Prolonged physical exercise is associated with several immunological changes, e.g. increase in proinflammatory cytokines, changes in the white blood count etc. Great discrepancies exist with regard to the exercise- induced influence on serum immunoglobulin and neopterin values. One explanation could be the shifts in plasma volume (PV) during and after exercise which might influence plasma concentrations of these parameters. Therefore we investigated the consequences of a marathon race in a homogenous group of experienced runners on plasma volume shifts, serum Immunglobulin and neopterin concentrations. Plasma values with and without correction for plasma volume shifts were compared. PV was significantly diminished after the race (-8.4%) followed by a rise 34h after finish (+8.5%). Serum immunoglobulin IgG, IgA and IgM were increased within the first hours postmarathon and normalized in the recovery period. When chages in PV were considered, only IgA rose significantly. Serum neopterin remained unchanged after the marathon independently whether corrected for PV changes or not. We conclude that the increase in immunoglobulins in our study was mainly the consequence of plasma volume changes. Since neopterin was unchanged we have at least in our study no evidence for exercise-induced activation of the cellular immune system.

Tetrahydrobiopterin (BH 4 ) is one of the cofactors for nitric oxide synthase (NOS), and also has a protective effect against reactive oxygen species (ROS)- and/or nitric oxide (NO)-induced cytotoxicities. Lipopolysaccharide (LPS) induces NO production and BH 4 synthesis, and also ROS release. This study examined whether hydrogen peroxide, one of the ROS, has a regulatory role in BH 4 synthesis in vascular endothelial cells. Addition of LPS to the endothelial cells increased the BH 4 content. Although the LPS-induced increase in BH 4 content was not affected by the treatment with superoxide dismutase and catalase, co-treatment with hydrogen peroxide further stimulated the LPS-induced increase in BH 4 content. Moreover, the hydrogen peroxide-induced increase in BH 4 content in the presence of LPS was completely inhibited by the treatment with 2,4-diamino-6-hydroxypyrimidine, an inhibitor of GTP-cyclohydrolase I (GTPCH). These findings suggest that hydrogen peroxide may stimulate LPS-induced BH 4 synthesis through the induction and/or activation of GTPCH. Under inflammation, hydrogen peroxide seems to stimulate BH 4 synthesis.

We investigated the effects of by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors, cerivastatin and fluvastatin, on the induction of nitric oxide (NO) production in vascular smooth muscle cells ( VSMC) stimulated by interleukin-1β (1L-1) or in combination with interferon-γ (IFN). IL-1 activated VSMC to synthesize and release NO, which was significantly potentiated by IFN. NO production induced by IL-1 or IL-1/lFN was dosedependently enhanced by both HMG-CoA reductase inhibitors. Incubating VSMC with IL-1/IFN stimulated inducible NO synthase (iNOS) mRNA expression. Both HMG-CoA reductase inhibitors significantly upreguiated IL/IFN-stimulated iNOS mRNA expression, and enhanced iNOS gene transcription as shown by nuclear run-on assays. Both IIMG-CoA reductase inhibitors slightly modulated IL-1/IFN-induced NF-kB activation, which was not associated with their effect on NO production. Cytokines induce the de novo synthesis of tetrahydrobiopterin (BH 4 ) in VSMC. This event is essential for the induction of NO synthesis, which requires transcriptional induction of the genes that encode not only iNOS but also guanosine triphosphate cyclohydrolase I (GTPCH), the first and rate-limiting enzyme in de novo BH 4 synthesis. The synthesis of BH 4 and GFPCH mRNA induced by IL-1/IFΝ were enhanced by both HMG-CoA reductase inhibitors. Exogenous mevalonate significantly prevented and geranylgeranylpyrophosphate reversed the stimulatory effect of HMG-CoA reductase inhibitors. Thus, the effect of HMG-CoA reductase inhibitors on NO production is due at least partly through blocking the biosynthesis of mevalonate, which prevents isoprenoid biosynthesis. Our data demonstrated that HMG-CoA reductase inhibitors enhance immunostimulants-induced NO production by increasing iNOS gene expression at the transcriptional level via an NF-kB-independent pathway. In addition to augmenting iNOS expression, HMG-CoA reductase inhibitors potentiate GTPCH gene expression and BH 4 synthesis, thereby prevents a relative shortage of BH 4 which may shift in the balance between NOS-catalyzed generation of protective NO and deletorious reactive oxygen species.

Vascular endothelial cells are one of the major biological targets of reactive oxygen species (ROS) in ischemiareperfusion, diabetes, hypercholesterolemia and inflammation. Accumulated evidence has shown that tetrahydrobiopterin (BH 4 ), which is an essential cefactor for nitric oxide synthase (NOS) activity, protected the cells against ROS and nitric oxide (NO) toxicities. Although NOS releases NO, which regulates vascular tone and immune surveillance under normal conditions, NOS also produces superoxide anion and hydrogen peroxide when BH 4 is decreased, suggesting the possibility that NOS is a source of ROS under pathological conditions. Since BH 4 is easily oxidized by ROS, oxidative stress may induce ROS release from NOS by the decomposition of BH 4 . BH 4 also has an antioxidative activity and scavenging activity for ROS. In this review, the r o l e of BH 4 in the function of' NOS, and the mechanisms underlying the protective effect of BH 4 against ROS- and/or NO-induced endothelial cell injury will be discussed.