Correlation of Serum Interferon Gamma and Neopterin Concentrations in Africans with Various Diseases
Gilbert ReibneggerDietmar FuchsArno HausenErich SchmutzhardErnst R. WernerGabriele Werner‐FelmayerManfred P. DierichHelmut Wächter
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Summary Concentrations of interferon gamma in serum and of neopterin in serum and urine were determined in 55 Tanzanians attending a local hospital for various diseases or complaints. For comparison, serum concentrations of interferon gamma and of neopterin were also measured in 76 clinically healthy Austrian blood donors. Both interferon gamma and neopterin concentrations were significantly higher in patients than in blood donors. Both analytes were significantly correlated with each other, and both exhibited similar behaviour in dependence on clinical diagnosis. The results support use of neopterin determination for indirect measurement of endogenous production of interferon gamma.Keywords:
Neopterin
Correlation of Serum Interferon Gamma and Neopterin Concentrations in Africans with Various Diseases
Summary Concentrations of interferon gamma in serum and of neopterin in serum and urine were determined in 55 Tanzanians attending a local hospital for various diseases or complaints. For comparison, serum concentrations of interferon gamma and of neopterin were also measured in 76 clinically healthy Austrian blood donors. Both interferon gamma and neopterin concentrations were significantly higher in patients than in blood donors. Both analytes were significantly correlated with each other, and both exhibited similar behaviour in dependence on clinical diagnosis. The results support use of neopterin determination for indirect measurement of endogenous production of interferon gamma.
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The efficacy of endogenous, exogenous, and combined endogenous-exogenous interferon was compared in the treatment of mice preinfected with 40–80 LD50 of EMC virus. The different interferon inducers, Newcastle Disease virus, statolon, and poly (I) poly (C) proved equally effective in increasing the survival of viral infected mice. Daily reinoculation of an inducer afforded no significant added protection. Administration of potent interferon preparations proved more effective than any of the interferon inducers in 3 experiments and equally effective in a fourth experiment. In 2 experiments no significant difference was observed between the therapeutic efficacy of combined endogenous-exogenous interferon and exogenous interferon alone, whereas in a third experiment the combined treatment proved more effective. A combined interferon treatment initiated 18 or 24 hr after inoculation of 2.5 or 8 LD50 of EMC virus still afforded a significant degree of protection.
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Human umbilical vein endothelial cells (HUVEC) were investigated for their ability to produce neopterin, a biochemical marker for an activated immune system. Interferon-gamma (IFN-gamma), IL-1 alpha, IL-2, IL-6, tumour necrosis factor-alpha, granulocyte/macrophage colony stimulating factor, phytohaemagglutinin and concanavalin A were used to stimulate HUVEC. While IFN-gamma induced neopterin release from HUVEC in a time- and dose-dependent manner, all the other cytokines used had no effect on neopterin production. High neopterin levels are found in patients with rejection episodes or infections. Our results suggest that not only monocytes and macrophages, which are known to synthesize neopterin, but also endothelial cells are responsible for these high serum neopterin levels.
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Phytohaemagglutinin
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We compared tryptophan, neopterin, and interferon-γ (IFN-γ) concentrations in serum and cerebrospinal fluid (CSF) of 22 patients with human immunodeficiency virus type 1 (HIV-1) infection. Tryptophan levels were found to be decreased in CSF and serum of patients whereas neopterin levels in CSF and serum and serum IFN-γ concentrations were increased compared to healthy HIV-1 seronegatives. Tryptophan concentrations correlated negatively to neopterin concentrations, and serum neopterin concentrations correlated positively to IFN-γ concentrations. Thus, decrease of tryptophan levels is associated with chronic immune stimulation in patients with HIV-1 infection. From the data it appears that reduced tryptophan in patients may result from induction of indoleamine (2,3)-dioxygenase by IFN-γ.
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In order to investigate the role of endogenous interferon in retrovirus production by infected or induced cells, the effect of two sera raised against mouse interferon has been tested on various C-type murine viruses. Addition of a highly potent anti-interferon serum to 3T3/IC cells chronically infected by the Moloney strain of MLV results in a considerable increase of virus production, as tested by reverse transcriptase assay. This effect is neutralized by an excess of exogenous interferon. The greatest effect of anti-interferon sera was obtained in the derepression of endogenous retroviruses: in K. BALB/c cells treated by IUDR, anti-interferon serum increases up to 50-fold the expression of the endogenous virus. The extinction of virus production which secondarily occurs after its induction by IUdR is likely to be caused by cellular endogenous interferon. The biological parameters of the viral agent produced in the presence of anti-interferon serum are those of the xenotropic endogenous virus.
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The production of neopterin is closely correlated with activation of cell-mediated immunity. Neopterin appears to be produced by human macrophages specifically stimulated with interferon-gamma (IFN-gamma). Interleukin-4 (IL-4), a B and T stimulatory factor, has recently been shown to inhibit monocyte/macrophage functions, including the ability to suppress monocyte-generated cytokines. In this report we confirmed previous studies that identified the monocyte/macrophage as the main producing cell among human blood cells and that secretion is stimulated by IFN-gamma and lipopolysaccharides (LPS). IL-4 inhibits the generation of neopterin from unstimulated monocytes. This inhibitory effect was dose dependent and occurred at concentrations lower than 0.01 ng/ml. However, IL-4 had only a minimal inhibitory effect on LPS-induced generation of neopterin and could not reverse IFN-gamma-induced neopterin secretion from adherent monocytes. Furthermore, we report that LPS induced IFN-gamma production in monocyte culture. This production is strongly inhibited by IL-4 treatment. These findings indicate that IL-4 can regulate the synthesis of neopterin by adherent blood mononuclear cells and provide further evidence that LPS-induced neopterin in macrophages may act by IFN-gamma-independent mechanisms.
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We have recently shown that interferon-gamma is capable of activating the key enzyme of pterin biosynthesis in macrophages. This leads to excretion of the stable degradation product neopterin (3). In this article we present experimental evidence suggesting that stimulation of T cells by alloantigens is associated with release of interferon-gamma—which, in the case of rejection, is locally restricted and not always detectable in the bloodstream. Neopterin induced by this lymphokine, however, readily penetrates tissue barriers and is detectable in the serum. This conclusion is based on two different sets of observations: (1) If supernatants of MLCs are compared with sera from patients with documented acute rejection episodes for their interferon-gamma and neopterin levels, a marked gradient is observed to exist between interferon levels measured in vitro and in vivo; this is not the case for neopterin for which comparable levels were seen. (2) Detection of interferon-gamma in sera of allograft recipients invariably precedes an increase of neopterin; on the other hand, increasing neopterin counts are also seen in the absence of detectable interferon-gamma levels in the serum. It thus appears that although interferon-gamma release during allograft rejection is primarily restricted to the tissue, evaluation of certain metabolites of interferon-dependent metabolic pathways enables definition of its endogenous release. Whereas interferon gamma represents a less reliable marker in the monitoring of rejection episodes, it might offer an additional means to differentiate rejection from systemic infections. Such a discrimination can not be achieved with the neopterin marker.
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Pterin
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Because of the difficulty encountered in identifying interferon in human urine during viral disease, the effect of urine on the biological activity of interferon in vitro was studied. Exogenous interferon was mixed with urine or control medium and incubated at 37 C for 4 hr. Subsequent assay of interferon revealed that the interferon exposed to urine had markedly less activity than the interferon exposed to control medium. The process of inactivation began immediately, was completed within 30 min, and was retarded at 4 C. Dialyzed urine did not inactivate interferon; of the dialyzable components of urine that were tested, only phenol, in expected urinary concentrations, reduced titers of interferon.
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Previous studies have indicated that neopterin is synthesized in vitro by human monocyte-derived macrophages and dendritic cells upon stimulation with gamma interferon (IFN-gamma). Neopterin production under specific conditions in vitro has also been obtained upon stimulation with IFN-alpha and/or IFN-beta. However, it is unknown if any IFN-gamma-independent neopterin synthesis is possible in vivo. In the present study we investigated the serum neopterin concentrations in patients affected by the syndrome of Mendelian susceptibility to mycobacterial disease (MSMD). Indeed, this syndrome is characterized by deeply impaired or absent IFN-gamma production or function due to severe mutations in molecules involved in IFN-gamma/interleukin-12 (IL-12)/IL-23-dependent pathway. Serum neopterin levels were measured by an enzyme-linked immunosorbent assay in 27 patients with MSMD. We found that serum neopterin levels are elevated in the complete absence of IFN-gamma activity due either to a complete deficiency of its receptor or to deleterious mutations of IL-12 or its receptor. These data clearly indicate that, as reported from in vitro studies, other stimuli are able to induce neopterin synthesis in vivo. Consequently, neopterin cannot be used as means of diagnosis of MSMD due to IFN-gamma-, IL-12-, and IL-23-dependent pathway defects.
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In this study, we further investigated a possible link between activation of cell-mediated immunity and anaemia in patients with haematological neoplasias. We compared serum concentrations of interferon-gamma and neopterin with haemoglobin levels. Significantly increased interferon-gamma and neopterin concentrations indicated persistent activation of cell-mediated immunity. Neopterin levels correlated significantly to interferon-gamma concentrations and inversely to haemoglobin levels. The data indicate an association between activated macrophages and the development of anaemia in patients with haematological neoplasias.
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Cellular immunity
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