Neopterin production and tryptophan degradation during 24-months therapy with interferon beta-1a in multiple sclerosis patients (original) (raw)
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Transplant Immunology, 2011
The anti-proliferative and immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO) degrades the essential amino acid tryptophan via the kynurenine pathway. IDO is stimulated during cellular immune responses preferentially by Th1-type cytokine interferon-γ (IFN-γ). IDO activity is estimated by calculating the kynurenine to tryptophan ratio (Kyn/Trp). In human monocyte-derived macrophages and dendritic cells, GTP-cyclohydrolase I is induced in parallel to IDO and produces neopterin. This study investigated the effects of common immunosuppressants on freshly isolated human peripheral blood mononuclear cells (PBMC) in vitro. PBMC were incubated with compounds for 30 min and then either left unstimulated or stimulated with mitogen phytohaemagglutinin (PHA). Concentrations of tryptophan, kynurenine and neopterin were measured in supernatants after 48 h. Kyn/Trp, neopterin and IFN-γ concentrations were significantly higher in PHA-stimulated vs. unstimulated PBMC. Tacrolimus (FK506), cyclosporine A (CsA), sirolimus and methylprednisolone dose-dependently inhibited tryptophan degradation and neopterin production. FK506, CsA and sirolimus showed significant inhibition at concentrations as low as 0.1 μg/ml, whereas prednisolone and methylprednisolone required higher doses to suppress tryptophan degradation. Mycophenolate-mofetil suppressed neopterin formation more efficiently than Kyn/Trp. All tested drugs also strongly decreased mitogen-induced IFN-γ concentrations. Overall the investigated immunosuppressants are effective to inhibit IDO activity and neopterin production in a similar and dose-dependent manner, however with some differences in IC50s when comparing individual compounds. The corresponding changes of IFN-γ concentrations are in line with its role as a trigger of both biochemical changes.
Journal of the European Academy of Dermatology and Venereology, 2009
Background Behcet's disease (BD) is a chronic, inflammatory, multisystem vasculitic disorder. There is no reliable laboratory marker that indicates disease activity. Neopterin is an immunological marker of cellular immune activation, which is secreted by monocytes/macrophages as a result of interferon-gamma (IFN-c) secretion by activated T lymphocytes. Objective We aimed to investigate serum and urine neopterin levels in BD patients. Methods Forty-five patients who were diagnosed according to the criteria of the International Study Group for BD and 45 age-and sex-matched healthy controls were enrolled in the study. Disease activity was considered by clinical findings. Serum and urine neopterin levels and serum IFN-c levels were measured. Results The mean values of serum and urine neopterin levels were 12.68 ± 4.87 nmol/L and 167.53 ± 148.73 lmol/mol creatinine, respectively, in BD patients (P ¼ 0.000 and P ¼ 0.008, respectively), which were statistically significantly different from the control group. However, there was no significant statistical difference between serum and urine neopterin levels of the clinically active and inactive patients. It was also found that the mean value of serum IFN-c levels was higher in healthy controls than in BD patients (P ¼ 0.000). Conclusions We conclude that serum and urinary neopterin measurement can not be used as a reliable laboratory marker as the BD patients' serum and urinary neopterin levels do not increase in the active stage even though these levels increase when compared to healthy controls.
Brain, 1997
The aim of this study was to assess neopterin, a marker of and controls, respectively. They also had a greater number of peaks in their serial UNCR measurements than controls interferon gamma (IFN-γ) induced macrophage activity, as (P Ͻ 0.001 for all patients and P Ͻ 0.01 for each group); a possible surrogate marker of inflammation in patients with the meansϮSD peaks/subject/month were: 2.1Ϯ1.8; 3.0Ϯ1.7; multiple sclerosis. Urinary neopterin to creatinine ratios 3.3Ϯ 2.3 and 0.2Ϯ 0.6 for PP, RR, SP patients and controls, (UNCRs) were measured daily in 10 primary progressive respectively. Nine relapses occurred in nine patients during (PP), 10 relapsing remitting (RR) and 11 secondary the study, and all were associated with increased neopterin progressive (SP) patients with multiple sclerosis, and 14 excretion, which tended to be greater than that on days not normal control (NC) subjects, for periods of up to 12 associated with a relapse. Three of the nine relapses were weeks. After excluding measurements related to infection, preceded by an upper respiratory tract infection. In eight out the median of the individuals' average UNCRs was of 13 patients who had infections during the study, increased significantly higher in patients than in controls (P Ͻ 0.001 neopterin excretion was noted for periods of up to 6 weeks for all patients and P Ͻ 0.01 for each of the three groups post-infection, significantly longer than that which occurred of patients); the median UNCRs (and interquartile ranges) after infections in controls. This confirms infection as a were 187 (135-231), 187 (165-277), 218 (164-517) and 134 potent inducer of symptomatic and asymptomatic disease (97-152) µmol/mol for PP, RR, SP patients and controls, activity in mutiple sclerosis, and provides further support of respectively. Similarly, patients had a greater median a pivotal role for IFN-γ in the pathogenesis of mutiple proportion of days with a UNCR above normal (P Ͻ 0.001 sclerosis. Urinary neopterin excretion is increased in patients for all patients and P Ͻ 0.01 for each group); the median with both progressive and relapsing mutiple sclerosis, and percentages (and interquartile ranges) were 16 (6-62), 28 therefore has potential as a surrogate marker of the inflammatory component of mutiple sclerosis disease activity. (21-36), 49 (14-86) and 0 (0-6)% for PP, RR, SP patients Abbreviations: EDSS ϭ expanded disability status scale; IFN-γ ϭ interferon gamma; PP ϭ primary progressive; RR ϭ relapsing remitting; SP ϭ secondary progressive; TNF-α ϭ tumour necrosis factor alpha; UNCR ϭ urinary neopterin to creatinine ratio
Interferon-alpha–induced changes in tryptophan metabolism
Biological Psychiatry, 2003
Background: Tryptophan (TRP) degradation into kynurenine (KYN) by the enzyme, indoleamine-2,3-dioxygenase, during immune activation may contribute to development of depressive symptoms during interferon (IFN)-␣ therapy. Methods: Twenty-six patients with malignant melanoma were randomly assigned in double-blind fashion to receive either placebo or paroxetine, beginning 2 weeks before IFN-␣ treatment and continuing for the first 12 weeks of IFN-␣ therapy. At treatment initiation and at 2, 4, and 12 weeks of IFN-␣ treatment, measurements of TRP, KYN, and neopterin (a marker of immune activation), were obtained, along with structured assessments of depression, anxiety, and neurotoxicity. Results: Regardless of antidepressant treatment status, all patients exhibited significant increases in KYN, neopterin, and the KYN/TRP ratio during IFN-␣ therapy. Among antidepressant-free patients, patients who developed major depression exhibited significantly greater increases in KYN and neopterin concentrations and more prolonged decreases in TRP concentrations than did nondepressed, antidepressant-free patients. Moreover, in antidepressantfree patients, decreases in TRP correlated with depressive, anxious, and cognitive symptoms, but not neurovegetative or somatic symptoms. No correlations were found between clinical and biological variables in antidepressant-treated patients. Conclusions: The results suggest that reduced TRP availability plays a role in IFN-␣-induced depressive symptoms, and paroxetine, although not altering the KYN or neopterin response to IFN-␣, attenuates the behavioral consequences of IFN-␣-mediated TRP depletion. Biol Psychiatry 2003;54:906 -914
Potential role of immune system activation-associated production of neopterin derivatives in humans
Inflammation Research, 2003
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-g. 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.
1990
Determination of neopterin lD-erythro-6-(l',2',3'-tnh\dro\)pro- pyl)pterin| in body fluids is a powerful diagnostic tool in a variety of diseases in which activation of cellular immune mechanisms is involved, such as certain malignancies, allograft rejection, and autoimmune and infectious diseases. In vitro, neopterin is released into the supernatant by peripheral blood-derived monocytes/macrophages upon stimulation with 7-interferon. In parallel, cleavage of tryptophan by
Cancer research, 1990
Determination of neopterin [D-erythro-6-(1',2',3'-trihydroxypropyl)pterin] in body fluids is a powerful diagnostic tool in a variety of diseases in which activation of cellular immune mechanisms is involved, such as certain malignancies, allograft rejection, and autoimmune and infectious diseases. In vitro, neopterin is released into the supernatant by peripheral blood-derived monocytes/macrophages upon stimulation with gamma-interferon. In parallel, cleavage of tryptophan by indoleamine 2,3-dioxygenase is induced. We report here that the human myelomonocytic cell line THP-1 forms neopterin and degrades tryptophan upon treatment with gamma-interferon. Like in macrophages alpha-interferon and beta-interferon induce these pathways only to a much smaller degree. The action of interferons is enhanced by cotreatment with tumor necrosis factor alpha, lipopolysaccharide, or dexamethasone. gamma-Interferon-induced neopterin formation and indoleamine 2,3-dioxygenase activity are ...
Tryptophan degradation and neopterin levels in treated rheumatoid arthritis patients
Clinical Rheumatology
Increased kynurenine/tryptophan—reflects trytophan degradation—and neopterin levels have been regarded as a biochemical marker of cell-mediated immune response and inflammation. This study was designed to evaluate the usefulness of tryptophan degradation and neopterin levels in active rheumatoid arthritis patients under therapy. In this case–control study, kynurenine and tryptophan levels were determined by HPLC; neopterin and tumor necrosis factor-α levels were measured with ELISA in 32 active rheumatoid arthritis patients and 20 healthy controls. Although mean values of tryptophan, kynurenine, ratio of kynurenine to tryptophan, neopterin, and tumor necrosis factor-α levels did not show statistically significant differences between patient and control groups, neopterin levels correlated positively with kynurenine (r = 0.582, p < 0.02), kynurenine/tryptophan (r = 0.486, p < 0.05), erythrocyte sedimentation rate (r = 0.472, p < 0.05) and RF (r = 0.478, p < 0.05) in the rheumatoid arthritis group. CRP levels of the patient group correlated with kynurenine levels (r = 0.524, p < 0.03). Determination of tryptophan degradation and neopterin levels in chronic inflammatory disease may provide a better understanding of progression of the disease.
Tryptophan degradation and neopterin levels by aging
Pteridines, 2013
Increased neopterin concentrations and altered tryptophan degradation are observed in diseases concomitant with cellular immune activation. This may be involved in the pathogenesis of several age-related disorders such as neurodegenerative disorders, autoimmune diseases, cardiovascular system disorders and malignancies. Therefore, in the present study, the evaluation of immune system activation by determination of tryptophan degradation and serum neopterin levels was carried out in volunteers aged ≥65 and <65 years old. The kynurenine-to-tryptophan ratio was calculated to estimate indoleamine-(2,3)-dioxygenase (IDO) activity. Tryptophan levels in the elderly (53.1±1.6 μmol/L) were lower than individuals under 65 years (61.4±2.2 μmol/L), whereas kynurenine concentrations in geriatrics and adults were 5.0±0.2 μmol/L and 4.3±0.2 μmol/L, respectively (both p<0.05). The kynurenine-to-tryptophan ratio was also significantly higher in geriatrics (92.1±3.2) than adults (73.5±2.8) (p&l...
Interferon-beta affects the tryptophan metabolism in multiple sclerosis patients
European Journal of Neurology, 2005
Tryptophan and its metabolites are of great interest in understanding the pathogenesis of multiple sclerosis (MS). The total levels of tryptophan and its metabolites, kynurenine and kynurenic acid were determined in plasma by capillary liquid chromatography electrospray ionisation tandem mass spectrometry. This is the first report of the plasma levels of these analytes in healthy controls and relapsing–remitting MS patients receiving long-term and acute interferon-β (IFN-β) treatment. Twenty-four hours post-administration increased kynurenine levels (first IFN MS versus healthy, P = 0.042) and kynurenine/tryptophan ratio (K/T; first IFN MS versus healthy, P =0.027; first IFN MS versus long-term IFN MS, P = 0.036) were found. The long-term IFN MS group had higher K/T ratios at 4 and 12 h post-administration (P = 0.015 and 0.009, respectively). The increase of K/T ratio in the first IFN MS group indicate an induction of the enzyme indolamine-2,3-dioxygenase (IDO), as reported earlier in experimental allergic encephalomyelitis. As IDO is participating in both inflammatory and neurodegenerative processes, further knowledge of its involvement in the pathogenesis of MS is of great importance.