PubMed Health⌕ Search

Biomedical subjects

G Baier-Bitterlich

Publications and source records attributed to G Baier-Bitterlich.

At least 37 records · Page 2Linked to original sources
PubMed1996

Role of neopterin and 7,8-dihydroneopterin in human immunodeficiency virus infection: marker for disease progression and pathogenic link.

Human immunodeficiency virus (HIV) infection is associated with increased concentrations of neopterin derivatives, released in large quantities by human macrophages on stimulation with interferon-gamma (INF-gamma). Neopterin concentrations thus inversely correlate with absolute CD4+ T-cell numbers and strongly predict progression of disease from latency to AIDS. Investigations of hydrogen peroxide-induced chemiluminescence indicated a potential role of neopterin and 7,8-dihydroneopterin in oxygen free radical-mediated processes. Indeed, 7,8-dihydroneopterin is able to enhance tumor necrosis factor alpha (TNF-alpha)-induced apoptosis, accompanied by an increased production of reactive oxygen intermediates (ROIs). In line with this finding, the same combination appears to contribute to the upregulation of HIV replication due to activation of nuclear factor-kappa B (NF-kappa B), a central enhancer element of the HIV LTR promoter. Thus, besides the role of neopterin as sensitive indicator of disease activity in HIV infection, neopterin derivatives apparently are associated with the cascade of events that regulate the HIV production in infected individuals.

Apoptosis↗
PubMed1996

Activated cellular immunity and decreased serum tryptophan in healthy pregnancy.

We analyzed plasma samples from 45 randomly selected healthy pregnant women and from 20 healthy nonpregnant female controls of corresponding age. Tryptophan and kynurenine concentrations were measured by reverse-phase high performance liquid chromatography. The kynurenine per tryptophan ratio was calculated to allow a more accurate estimate of tryptophan degradation. In addition, neopterin was measured by radioimmunoassay. There were significantly lower tryptophan concentrations in pregnant women compared to nonpregnant controls. Kynurenine per tryptophan ratios were increased in pregnant women in the 3rd trimester. Significant correlations existed between neopterin increase and tryptophan decrease as well as kynurenine increase and tryptophan decrease. Also significant correlations between week of pregnancy and lower tryptophan and higher kynurenine per tryptophan ratio were found (p < 0.01). From our data, cellular immune activation is likely to be the cause of enhanced tryptophan degradation during pregnancy.

Biopterins↗
PubMed1996

Decreased plasma tryptophan in pregnancy.

OBJECTIVE: To examine levels of serum tryptophan and its degradation product kynurenine in uncomplicated pregnancy, according to the week of pregnancy and the concentrations of neopterin. METHODS: Plasma was analyzed from 45 healthy pregnant women (15 in each trimester), 15 healthy puerperas, and 20 nonpregnant controls. Tryptophan and kynurenine were measured by reverse-phase, high-performance liquid chromatography, and neopterin by radioimmunoassay. RESULTS: In healthy pregnant women, tryptophan values decreased (median first trimester: 72 mumol/L; second trimester: 51 mumol/L; third trimester: 46 mumol/L; P < .001) in a manner correlated with the duration of pregnancy (Spearman rank correlation coefficient ra = -0.771, P < .001) and normalized in the puerperium (median 60 mumol/L). No change in kynurenine, a tryptophan degradation product, was observed, but the ratio of kynurenine to tryptophan increased during pregnancy and correlated positively with gestational age (ra = 0.714, P < .001). In addition, an inverse correlation existed between neopterin and tryptophan concentrations (ra = -0.566, P < .001), as well as a positive one between neopterin and the kynurenine to tryptophan ratio (ra = 0.660, P < .001). CONCLUSION: Tryptophan levels decrease during normal pregnancy and the decrease may be related to immune activation phenomena.

Biopterins↗
PubMed1996

Effects of neopterin-derivatives on H2O2-induced luminol chemiluminescence: mechanistic aspects.

Neopterin, 6-D-erythro-1',2',3'-trihydroxypropyl-pterin, and its dihydroform, 7,8-dihydro-neopterin, are synthesized by human monocytes/macrophages upon stimulation by interferon-gamma. In the presence of iron chelator complexes neopterin enhances hydrogen peroxide-induced luminol chemiluminescence at neutral or slightly alkaline pH (7.5). In contrast, 7,8-dihydroneopterin scavenges chemiluminescence independently from the pH value and iron. In this study, we explored in more detail the mechanism possibly involved: analysis of the reaction products shows that 7,8-dihydroneopterin is oxidized and degraded to 7,8-dihydroxanthopterin and xanthopterin, whereas the neopterin molecule is not chemically altered during the chemiluminescence reaction. Investigations of the neopterin-induced effect show that mannitol, a scavenger of hydroxyl radicals, does not alter the enhancing effect of neopterin. L-histidine, which scavenges singlet oxygen almost as effective as hydroxyl radicals, reduces the enhancing effect of neopterin. However, singlet oxygen was not detectable during the reaction by measuring monomol light emission (1270 nm). When replacing hydrogen peroxide by 3-morpholinosydnonimine, a generator of hydroxyl radicals, or naphthalene-endoperoxide, a generator of singlet oxygen, in the luminol chemiluminescence assay, neopterin shows no enhancing effect irrespective of the presence of iron-(III)-EDTA. The data suggest that neopterin enhances hydrogen peroxide-induced luminol chemiluminescence in the presence of iron-(III)-EDTA by formation of a catalytic complex that seems to favor the formation of oxygen intermediates which derive from hydrogen peroxide and react with luminol.

Biopterins↗
PubMed1996

Streptococcal erythrogenic toxins induce neopterin formation in human peripheral blood mononuclear cells but not in the human myelomonocytoma cell line THP-1.

We tested whether the exposure of human monocytic cells to streptococcal erythrogenic toxins A, B, C and a streptococcal-derived Mitogert BX is associated with synthesis of neopterin in vitro. Neopterin production was not induced when the human myelomono-cytoma cell line THP-1 was stimulated with these toxins, and there was only a slight co-stimulatory effect of streptococcal erythrogenic toxin A together with interferon-gamma stimulation. However, these toxins induced interferon-gamma and further neopterin production in peripheral blood mononuclear cells of three healthy individuals. This neopterin formation could be blocked by anti-human interferon-gamma. From our investigations we conclude that there is no direct effect of streptococcal erythrogenic toxins on neopterin production by monocytic cells. However, the data obtained in peripheral blood mononuclear cell culture imply that these toxins are able to stimulate neopterin production in humans via the induction of huge amounts of interferon-gamma.

Biopterins↗
PubMed1996

7,8-Dihydroneopterin upregulates interferon-gamma promoter in T cells.

Activated cell-mediated immunity is accompanied by elevated concentrations of interferon-gamma leading to the secretion of neopterin-derivatives which are known as sensitive immune activation markers in clinical laboratory diagnosis. Recent data imply a potential role of neopterin-derivatives in oxygen-free radical-mediated processes and a direct impact of 7,8-dihydroneopterin on tumor necrosis factor alpha-mediated programmed cell death. We report here that 7,8-dihydroneopterin and hydrogen peroxide upregulate the production of interferon-gamma, thereby establishing an autocrine feed-back loop. Data put emphasis on the role of neopterin-derivates within the cytokine network.

Antioxidants↗
PubMed1996

Protein kinase C-theta isoenzyme selective stimulation of the transcription factor complex AP-1 in T lymphocytes.

T-lymphocyte stimulation requires activation of several protein kinases, including the major phorbol ester receptor protein kinase C (PKC), ultimately leading to induction of lymphokines, such as interleukin-2 (IL-2). The revelant PKC isoforms which are involved in the activation cascades of nuclear transcription factors involved in IL-2 production have not yet been clearly defined. We have examined the potential role of two representative PKC isoforms in the induction of the IL-2 gene, i.e., PKC-alpha and PKC-theta, the latter being expressed predominantly in hematopoietic cell lines, particularly T cells. Similar to that of PKC-alpha, PKC-theta overexpression in murine EL4 thymoma cells caused a significant increase in phorbol 12-myristate 13-acetate (PMA)-induced transcriptional activation of full-length IL-2-chloramphenicol acetyltransferase (CAT) and NF-AT-CAT but not of NF-IL2A-CAT or NF-kappaB promoter-CAT reporter gene constructs. Importantly, the critical AP-1 enhancer element was differentially modulated by these two distinct PKC isoenzymes, since only PKC-theta but not PKC-alpha overexpression resulted in an approximately 2.8-fold increase in AP-1-collagenase promoter CAT expression in comparison with the vector control. Deletion of the AP-1 enhancer site in the collagenase promoter rendered it unresponsive to PKC-theta. Expression of a constitutively active mutant PKC-theta A148E (but not PKC-alpha A25E) was sufficient to induce activation of AP-1 transcription factor complex in the absence of PMA stimulation. Conversely, a catalytically inactive PKC-theta K409R (but not PKC-alpha K368R) mutant abrogated endogenous PMA-mediated activation of AP-1 transcriptional complex. Dominant negative mutant Ha-RasS17N completely inhibited the PKC-O A148E-induced signal, PKC-O. Expression of a constitutively active mutant PKC-O A148E (but not PKC-alpha A25E) was sufficient to induce activation of AP-1 transcription factor complex in the absence of PMA stimulation. Conversely, a catalytically inactive PKC-O K409R (but not PKC-alpha K368R) mutant abrogated endogenous PMA-mediated activation of AP-1 transcriptional complex. Dominant negative mutant Ha-enRasS17N completely inhibited in the PKC-O A148E-induced signal, identifying PKC-theta as a specific constituent upstream of or parallel to Ras in the signaling cascade leading to AP transcriptional activation.

Animals↗
PubMed1995

Effect of neopterin and 7,8-dihydroneopterin on tumor necrosis factor-alpha induced programmed cell death.

Tumor necrosis factor-alpha and the formation of reactive oxygen intermediates are central mediators of apoptosis. Recent data indicated a role of neopterin and 7,8-dihydroneopterin in oxygen radical mediated processes. We have therefore investigated the effect of neopterin-derivatives on TNF alpha induced apoptosis of the monocyte-like cell line U937. At an elevated concentration 7,8-dihydroneopterin was found to superinduce TNF alpha mediated programmed cell death due to the formation of reactive oxygen intermediates. Our results imply that in combination with TNF alpha high concentrations of 7,8-dihydroneopterin enhances apoptosis due to oxidative stress on cells.

Acetylcysteine↗
PubMed1995

The role of p56lck in CD4-mediated suppression of CD3-induced early signaling events in T lymphocytes.

Crosslinking of the CD4 coreceptor can inhibit subsequent T-cell activation via the T-cell antigen receptor (TCR)/CD3 complex. The ability of the human immunodeficiency virus (HIV) envelope protein, gp 120, to cause similar inhibition has implicated this inhibitory signal in the induction of T-cell anergy and apoptosis observed in the acquired immunodeficiency syndrome (AIDS). In order to clarify the biochemical basis of this inhibition, we analyzed the effect of CD4 ligation on early signaling events induced by subsequent CD3xCD4 co-crosslinking. By comparison with CD3 crosslinking alone, CD3xCD4 co-crosslinking of a CD3+CD4+ human T-cell leukemia line (SupT1) resulted in an enhanced increase in free intracellular calcium concentration and tyrosine phosphorylation of several cellular substrates, including the prominent phosphorylation of an unidentified 120-kDa protein (p120). Prior CD4 ligation inhibited these responses. Similar results were obtained with A3.01, another CD3+CD4+ T leukemic line. However, P120 was only minor phosphorylated on tyrosine upon receptor crosslinking in A2.01/CD4(-cyt401), a derivative line expressing a truncated CD4 coreceptor lacking its cytoplasmic domain which binds the p56lck protein tyrosine kinase (PTK). Furthermore, prior CD4 ligation failed to inhibit in this line the increased tyrosine phosphorylation induced by subsequent CD3xCD4 co-crosslinking. Thus, prior CD4 crosslinking, or expression of truncated CD4, are both associated with reduced p120 phosphorylation. These results suggest that p120 is a p56lck substrate playing an important role during T-cell activation.

CD3 Complex↗
PubMed1995

Inhibition of HIV-1 expression by HIV-2.

HIV-1 and HIV-2 are co-endemic in certain geographic areas. HIV-2 is more weakly pathogenic than HIV-1, and progression to AIDS occurs less frequently and over a longer period of time. Recent epidemiologic studies suggest that individuals infected with HIV-2 have a lower risk of HIV-1 infection. Both immune mechanisms and various modes of viral interference have been proposed to account for these results. Our findings, described in this paper, suggest that HIV-2 inhibits HIV-1 replication. To study the molecular interactions between HIV-1 and HIV-2, proviral clones were transfected alone or in combination into the human T cell line CEM. LTR-CAT indicator constructs were included for the purpose of monitoring viral promoter activity. Viral replication in transfected cells was monitored by p24 antigen capture assay of cell culture supernatants and Western blot analysis of cell extracts. HIV-2 inhibited HIV-1 replication as determined by intracellular and extracellular p24 antigen levels. Similar results were obtained with simultaneous virus infection using HIV-1 and HIV-2, rather than transfections of proviral DNA. Using cotransfection of HIV-1 and HIV-2 LTR indicator gene constructs, the mechanism of inhibition was found to be suppression of the HIV-1 LTR by HIV-2. The inhibitory effect of HIV-2 is not due to Tat-2, but appears to discriminate between the HIV-1 and HIV-2 LTRs based on differences in the Tat activation response element, TAR. These results suggest both a molecular mechanism for HIV-2 interference with HIV-1 replication and a potential molecular approach to therapy.

Base Sequence↗
PubMed1995

FAS-induced apoptosis is mediated via a ceramide-initiated RAS signaling pathway.

Fas receptor-induced apoptosis plays critical roles in immune homeostasis. However, most of the signal transduction events distal to Fas ligation have not been elucidated. Here, we show that Ras is activated following ligation of Fas on lymphoid lines. The activation of Ras is a critical component of this apoptotic pathway, since inhibition of Ras by neutralizing antibody or a dominant-negative Ras mutant interfered with Fas-induced apoptosis. Furthermore, ligation of Fas also resulted in stimulation of the sphingomyelin signalling pathway to produce ceramides, which, in turn, are capable of inducing both Ras activation and apoptosis. This suggests that ceramides acts as second messengers in Fas signaling via Ras. Thus, ligation of the Fas molecule on lymphocyte lines induces activation of Ras via the action of ceramide, and this activation is necessary, but not sufficient, for subsequent apoptosis.

Animals↗