Effects
Neopterin
derivatives interfere with reactive oxygen species and modulate
intracellular redox-sensitive signal-transduction cascades in vitro.
Potential
role of immune system activation-associated production of neopterin
derivatives in humans
Hoffmann G, et al. Institute for Physiology, University of Bonn,
Bonn, Germany
(Inflamm Res 2003; 52:
313-21)
Neopterin derivatives
are produced by human monocyte-derived macrophages and dendritic cells upon
stimulation with interferons. Neopterin concentrations measured in urine or
blood reflect activation of cellular immunity and endogenous release of
interferon-gamma. This review focuses on the clinical utility of measuring
neopterin levels in inflammatory disease and the potential functions of
neopterin as a mediator and/or modulator in the course of inflammatory and
infectious processes. In vitro-studies revealed that neopterin derivatives
exhibit distinct biochemical effects, most likely via interactions with
reactive oxygen or nitrogen intermediates, thereby affecting the cellular
redox state. Data support the hypothesis that the release of neopterin
enhances the cytotoxic potential of activated macrophages and dendritic
cells. In vivo, a strong correlation between neopterin levels and the
severity, progression, and outcome of infectious and inflammatory diseases
was found. The influence of neopterin derivatives on the cellular
metabolism may provide an explanation for these clinical observations.
Influence
of neopterin on the generation of reactive oxygen species in human
neutrophils
Razumovitch JA, et al. Department of Biophysics, Physics Faculty,
Belarus State University, Minsk, Belarus
(FEBS Lett 2003; 549: 83-6)
Neopterin is synthesized by human monocyte-derived macrophages primarily
upon stimulation with the cytokine interferon-gamma. We studied the
influence of neopterin on the generation of reactive oxygen species (ROS)
in human peripheral blood neutrophils. Radical formation was measured using
a biochemiluminometer. Neutrophils were isolated from peripheral blood of
healthy donors. The generation of ROS by neutrophils suspended in Earl's
solution (pH=7.4) at 37 degrees C was investigated by monitoring of
chemiluminescence using luminol and lucigenin as light emitters. Neopterin
induced chemiluminescence in suspensions of neutrophils in the presence of
luminol, but not of lucigenin. Neopterin affected only adhesive cells.
Addition of neopterin into the suspension of the cells involving
D-mannitol, L-histidine and diazabicyclo[2.2.2]octane (DABCO) decreased
luminol-dependent chemiluminescence (LDCL) of the neutrophils. The action
of superoxide dismutase (SOD) and
2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO) reduced
neopterin-induced LDCL of neutrophils. Data suggest that neutrophils
respond on exposure to neopterin with additional generation of singlet
oxygen, hydroxyl radical and nitric oxide by nicotinamide adenine
dinucleotide phosphate (NADPH)-independent pathways.
Neopterin
modulates toxicity mediated by reactive oxygen and chloride species
Weiss G, et al. Department of Internal Medicine, University of
Innsbruck, Austria
(FEBS Lett 1993; 321: 89-92)
Neopterin, a pyrazino-pyrimidine derivative, is synthesized in excess by
human monocytes/macrophages upon stimulation with interferon-gamma, a
cytokine derived from activated I cells. Neopterin is furthermore produced
constitutively. A relatively constant ratio between neopterin and its
reduced form. 7,8-dihydroneopterin, has been described in human serum. In
the study presented here we tested the ability of neopterin and its reduced
form to modulate the effects of cytotoxic substances like hydrogen peroxide
or hypochlorous acid and N-chloramine derivatives. We show that
7,8-dihydroneopterin potently reduces biological and chemical effects of
these substances independently from the pH value. In contrast, at slightly
alkaline pH (pH 7.5) neopterin enhances hydrogen peroxide and chloramine-T
activity. This is demonstrated by increase of signal intensity in a luminol
assay and also by enhancement of toxicity towards bacteria. Thus, the
macrophage derived substance neopterin is able both to enhance and to
reduce cytotoxicity in dependence of pH value and its oxidation state, and
it may have a pivotal role in modulation of macrophage mediated effector
mechanism.