Indian Journal of Occupational and Environmental Medicine   Official publication of Indian Association of  0ccupational  Health  
 Print this page Email this page   Small font sizeDefault font sizeIncrease font size
 Users Online:17

  IAOH | Subscription | e-Alerts | Feedback | Login 

Home About us Current Issue Archives Search Instructions
  Search
 
   Next article
   Previous article 
   Table of Contents
  
 
    Similar in PUBMED
     Search Pubmed for
     Search in Google Scholar for
   Related articles
    Article in PDF (179 KB)
    Citation Manager
    Access Statistics
    Reader Comments
    Email Alert *
    Add to My List *
* Registration required (free)  


   Abstract
   Introduction
   Mechanism of Neo...
   Oxidative Stress...
   Activation of Ne...
   Neurotransmitter...
   Neopterin and Di...
   Conclusion
   Acknowlegment
   References
   Article Figures
   Article Tables

 Article Access Statistics
    Viewed3336    
    Printed218    
    Emailed0    
    PDF Downloaded379    
    Comments [Add]    
    Cited by others 8    

Recommend this journal

 


 
REVIEW ARTICLE
Year : 2008  |  Volume : 12  |  Issue : 3  |  Page : 107-111
 

Neopterin: Biomarker of cell-mediated immunity and potent usage as biomarker in silicosis and other occupational diseases


National Institute of Miner's Health, JNARDDC Campus, Nagpur, India

Correspondence Address:
Shubhangi K Pingle
Research Officer, National Institute of Miners' Health, JNARDDC Campus, Wadi, Nagpur - 440 023
India
Login to access the Email id


DOI: 10.4103/0019-5278.44690

PMID: 20040967

Get Permissions

 

  Abstract 

Neopterin is regarded as an early biomarker of the cellular immune response. This low molecular mass compound belongs to the class of pteridine and is a metabolite of guanosine triphosphate, which is produced by the activated macrophages and dendritic cells after stimulation with γ-interferon. An international group acknowledges the fact that the levels of serum neopterin can be used as a marker of the effect of exposure to silica and other occupational diseases. The determination of neopterin is an innovative tool for monitoring diseases associated with the activation of cell-mediated immunity.


Keywords: Biomarker, cell-mediated immunity, γ-interferon, neopterin, silicosis, tryptophan degradation


How to cite this article:
Pingle SK, Tumane RG, Jawade AA. Neopterin: Biomarker of cell-mediated immunity and potent usage as biomarker in silicosis and other occupational diseases. Indian J Occup Environ Med 2008;12:107-11

How to cite this URL:
Pingle SK, Tumane RG, Jawade AA. Neopterin: Biomarker of cell-mediated immunity and potent usage as biomarker in silicosis and other occupational diseases. Indian J Occup Environ Med [serial online] 2008 [cited 2014 Jul 24];12:107-11. Available from: http://www.ijoem.com/text.asp?2008/12/3/107/44690



  Introduction Top


Neopterin [D-erythro-6-(1',2',3'-trihydroxypropyl)-pterin] [1] is known to be in equilibrium with 7,8-dihydroneopterin, and the presence of a high concentration of both oxidized and reduced forms of pteridin may be associated with oxidative stress. Silica is one of the most documented contaminants of the work place. Long-term occupational exposure to silica is associated with an increased risk for respiratory diseases such as silicosis, tuberculosis, chronic bronchitis, chronic obstructive pulmonary disease and lung cancer. [2] Furthermore, a variety of immune dysfunction-related diseases have been reported in the silicotic individual. Preliminary studies indicating an enhanced level of autoantibody and several cytokines reflect an involvement of the immune system in the pathogenesis of silicosis and the resulting complication as an early and valuable marker of cellular immunity. [2] Neopterin levels can be used as a marker of the effect of exposure to silica. [3]

Neopterin is pyrazino-pyrimidine compound of molecular weight 253 D belonging to the class of pteridines. Pteridine is a chemical compound of fused pyrimidine and pyrizine rings. A pteridine is a group of heterocyclic compounds containing a wide variety of substitutions in this structure. [4] Pterins and flavins are a class of substituted pteridines that have important biological activities. [4] It is produced by guanosine triphosphate (GTP) via γ-interferon (INF-γ) following the activation of T cells. Neopterin concentration increase in the urine or blood reflects the activation of cellular immunity and an endogenous release of INF-γ. [5] This review focuses on the clinical utility of measuring the neopterin levels in inflammatory diseases and the potential functions of neopterin as a mediator and modulator in the course of inflammatory and infectious processes. In vitro studies reveal that neopterin derivatives exhibit distinct biochemical effects, most likely via interactions with reactive oxygen or nitrogen intermediates, thereby affecting the cellular redox state. [5] Neopterin enhances the cytotoxic potential of the activated macrophages (AC) and the dendritic cells (DC). In vivo, a strong correlation was obtained between the neopterin levels and the disease severity, progression and outcome of infections with inflammatory disease. The influence of neopterin derivatives on the cellular metabolism may provide an explanation for these clinical observations.


  Mechanism of Neopterin Activation Top


Neopterin is derived from GTP and is produced by stimulated macrophages under the influence of INF-γ of lymphocyte origin. Cleavage of GTP by GTP-cyclohydrolase I results in neopterin, yielding 7,8-dihydroneopterin triphosphate, which is a joint precursor of dihydroneopterin, neopterin, tetrahydrobiopterin, a necessary cofactor of aromatic amino acid monooxygenase, and nitric oxide synthases (NOS). Human monocytes/macrophages are the unique source to produce an excess of neopterin derivatives at the rate of 5, 6, 7, 8-tetrahydrobiopterin, [6] which results as a comparably low activity of 6-pyrovoyltetrahydropterin synthase, which is the first enzyme in the conversion of 7,8-dihydroneopterin triphosphate to tetrahydrobiopterin. [7] On activation of the cellular immunity, IFN-γ induces GTP-cyclohydrolase I and also stimulates the enzyme indoleamine (2, 3)-dioxygenase (IDO) in various cells. [8],[9] In tryptophan catabolism, N-formyl-kynurenine, the first intermediate, is formed in response to IDO within the biosynthetic pathway of nicotinamide dinucleotide. To monitor the activation status of IDO and of cellular immunity, determination of kynurenine and tryptophan concentrations has proven to be a sensitive estimate both in vivo and in vitro [10],[11] [Figure 1].


  Oxidative Stress and Neopterin Top


Recent data suggest that neopterin derivatives exhibit distinct biochemical functions. Neopterin was found to enhance the effects of toxic reactive oxygen species originating from chloramine T and hydrogen peroxide, [12],[13] suggesting that neopterin derivatives are able to modulate macrophage-induced cytotoxicity by the induction of oxidative stress. In rat vascular smooth muscle cells, neopterin stimulates redox-sensitive intracellular signal transduction cascades, thereby triggering the inducible NOS (iNOS) gene expression at the messenger ribonucleic acid level with a subsequent increase in nitric oxide (NO) production. [14] In vascular muscle cells [15] and Jurkat cells, [16] the neopterin derivatives were found to activate the transcriptional nuclear factor (NF)-κB. It has been shown to induce programmed cell death, which is mediated by the reactive oxygen intermediates in T-lymphoblastic cell lines and in rat alveolar cells. [15],[16] In regard to these multiple biochemical functions of neopterin derivatives, it is very likely that DC might also use neopterin derivatives in the regulation of T cell response. Uniquely, in humans and primates, high concentrations of neopterin are detected during cellular immune activation produced by AM and also by DC. In all other organisms, activation of cellular immunity is accompanied by an increased production of tetrahydrobiopterin, an essential cofactor for iNOS. NO production by iNOS seems to play a role in inflammation, e.g., by acting regulatorily on NF-κB, an important modulator of inflammatory gene expression, including pro-inflammatory cytokines and endothelial cell adhesion molecules. [17] The production of neopterin derivatives instead of biopterin derivatives in humans suggest that neopterin derivatives substitute regulatory and immunological functions, especially of the tetrahydrobiopterin-induced NO generation.

DC produces neopterin derivatives on stimulation, which is additionally determined by the degree of IDO-dependent tryptophan degradation. As observed, neopterin production and IDO activation were found to closely correlate in a large variety of diseases in vivo, including systemic lupus erythematosus, hepatitis immunodeficiency virus and in pregnancy. [10],[18],[19]


  Activation of Neopterin by INF Affects the Immune System Top


To activate the gene transcription by initiation of intracellular signaling via a complex mechanism, INF binds to specific cell surface receptors. The gene gets modulated by INF stimulation and effects on inhibition of viral replication, cell proliferation and immunomodulation in infected cells. An effector protein such as neopterin and 2', 5'-oligoadeylates synthetase gets stimulated by INF. Neopterin has been used in the INF studies to demonstrate its immune activation by the INF. Neopterin has been validated in a large number of studies as a marker of INF activation. The level of neopterin increases with the INF. [20]


  Neurotransmitters and Neopterin Top


Occupational exposure to lead affects the neuromuscular junctions and it might cause disturbances in the locomotor activity. This study was carried out to evaluate pteridine metabolism for the synthesis of neurotransmitters in urinary neopterin, biopterin, creatinine and blood dihydropteridine reductase (DHPR) activity in battery workers and the delta-aminolevulonic acid (delta-ALA) was measured. Blood and urine lead levels were detected by an atomic absorption spectrophotometer. A significant increase in the blood and urine lead levels shows traces of urinary neopterin, biopterin and delta-ALA among exposed workers. [21] DHPR activity was indifferent as compared with the control group. These studies demonstrate that an increased activity of the pteridine pathway causes accumulation of the neurotransmitters, which may be responsible for the neurological disorders. [22]


  Neopterin and Different Diseases Top


It has been suggested that it is an excellent marker for the activation of the monocyte/macrophage axis in some clinical situations. Increased amounts of neopterin in body fluids are associated with a variety of diseases in which activation of the cellular immune mechanism is involved, such as certain malignancies, allograft rejection, autoimmune diseases and viral infections. [1],[23],[24],[25] Elevated neopterin levels were observed in silicotic individuals, [2],[26] rheumatoid arthritis (RA), [27] neuropsychiatric abnormalities, [28] Kaposi's sarcoma, [29] intrahepatic cholestasis of pregnancy, [30] pulmonary tuberculosis and follow-up of antituberculosis treatment, [31] activation of cell-mediated immunity (CMI) during pregnancy [32] and severe burn sepsis. [33] Neopterin and its reduced form modulate the cytotoxic substances, and it also leads to the generation of singlet oxygen, hydroxyl radical and NO. [12],[34] [Table 1]


  Conclusion Top


The most important clinical application of the determination of neopterin is as a prognostic indicator and as a follow-up for chronic infection, immune stimulation monitoring, differential diagnosis of acute bacterial and viral infection and also as an early indication for the complication of allograft recipient. [23],[24] As the neopterin level serves as an indirect indicator for oxidative stress, the CMI marker, the levels of neopterin help in the diagnosis of different diseases. [5] Elevated levels in the serum of the silicotic patients and the correlation of baseline neopterin with IFN will help in more advances in occupational diseases. [35] In RA, an immune dysregulation alters the release of neopterin from human monocytes/macrophages. [27] The increased formation of neopterin and degradation of tryptophan may result in a decreased T cell response along with the development of "immunodeficiency". [36] Pteridins are used as biochemical markers of immune system activation, mainly the markers of early activation and development of CMI response, which are used for the evaluation of pathologic disturbances. From the above studies, it may be concluded that elevated levels of neopterin can be used as a biomarker of CMI, silicosis and other occupational diseases.


  Acknowlegment Top


The authors are indebted to Dr. Jyoti Mukhopadhyay, Director, National institute of Miner's Health, Wadi, Nagpur, for rendering her fruitful suggestions, support and encouragement.

 
  References Top

1.Werner-Felmayer G, Werner ER, Fuchs D, Hausen A, Reibnegger G, Wachter H. Neopterin formation and tryptophan degradation by a human myelomonocytic cell line (THP-1) upon cytokine treatment. Cancer Res 1990;50:2863-7.  Back to cited text no. 1  [PUBMED]  [FULLTEXT]
2.Altindag ZZ, Baydar T, Isimer A, Sahin G. Neopterin as a new biomarker for the evaluation of occupational exposure to silica. Int Arch Occup Environ Health 2003;76:318-22.  Back to cited text no. 2  [PUBMED]  [FULLTEXT]
3.Gulumian, G, Murray J, Nelson G, Darvin L, Valliathan V, Castranova V, et al. Biomarkers of silicosis. Vilnius: International EUROGIN-EAST Conference; 2001.  Back to cited text no. 3    
4.Voet D, Voet JG. Biochemistry. 3rd ed. John Wiley and Sons, ISBN; 2004. p. 39223-5.  Back to cited text no. 4    
5.Feldman DM. Neopterin a novel marker of immune function in hepatitis C. Available from: http://www.hcvadvocate.org/hcsp/articles/feldman-1.html. October 9, 2008.  Back to cited text no. 5    
6.Huber C, Batchelor JR, Fuchs D, Hausen A, Lang A, Niederwieser D, et al. Immune response-associated production of neopterin: Release from macrophages primarily under control of interferon gamma. J Exp Med 1984;60:310-6.  Back to cited text no. 6    
7.Werner ER, Werner-Felmayer G, Fuchs D, Hausen A, Reibnegger G, Yim JJ, et al. Tetrahydrobiopterin biosynthetic activities in human macrophages, fibroblasts, THP-1, and T 24 cells: GTP-cyclohydrolase I is stimulated by interferon-gamma, and 6-pyruvoyl tetrahydropterin synthase and sepiapterin reductase are constitutively present. J Biol Chem 1990;265:3189-92.  Back to cited text no. 7  [PUBMED]  [FULLTEXT]
8.Werner ER, Bitterlich G, Fuchs D, Hausen A, Reibnegger G, Szabo G, et al. Human macrophages degrade tryptophan upon induction by interferon-gamma. Life Sci 1987;41:273-80.   Back to cited text no. 8  [PUBMED]  
9.Werner-Felmayer G, Werner ER, Fuchs D, Hausen A, Reibnegger G, Wachter H. Characteristics of interferon-induced tryptophan metabolism in human cells in vitro. Biochim Biophys Acta 1989;1012:140-7.   Back to cited text no. 9  [PUBMED]  [FULLTEXT]
10.Fuchs D, Mφller AA, Reibnegger G, Stφckle E, Werner ER, Wachter H. Decreased serum tryptophan in patients with HIV-1 infection correlates with increased serum neopterin and with neurologic/psychiatric symptoms. J Acquir Immune Defic Syndr 1990;3:873-6.   Back to cited text no. 10    
11.Huengsberg M, Winer JB, Gompels M, Round R, Ross J, Shahmanesh M. Serum kynurenine-to-tryptophan ratio increases with progressive disease in HIV-infected patients. Clin Chem 1998;44:858-62.  Back to cited text no. 11  [PUBMED]  [FULLTEXT]
12.Weiss G, Fuchs D, Hausen A, Werner ER, Semenitz E, Dierich MP, Wachter H. Neopterin modulates toxicity mediated by reactive oxygen and chloride spcies. FEBS Lett 1993;321:89-92.   Back to cited text no. 12  [PUBMED]  [FULLTEXT]
13.Murr C, Fuchs D, Gφssler W, Hausen A, Werner ER, Esterbauer H, et al. Enhancement of hydrogen peroxide-induced luminol-dependent chemiluminescence by neopterin depends on the presence of iron chelator complexes. FEBS Lett 1994;338:223-6.  Back to cited text no. 13    
14.Schobersberger W, Hoffmann G, Grote J, Wachter H, Fuchs D. Induction of inducible nitric oxide synthase expression by neopterin in vascular smooth muscle cells. FEBS Lett 1995;377:461-4.   Back to cited text no. 14  [PUBMED]  [FULLTEXT]
15.Schobersberger W, Hoffmann G, Hobisch-Hagen P, Bφck G, Vφlkl H, Baier-Bitterlich G, et al. Neopterin and 7,8-dihydroneopterin induce apoptosis in the rat alveolar epithelial cell line L2. FEBS Lett 1996;397:263-8.   Back to cited text no. 15    
16.Baier-Bitterlich G, Fuchs D, Murr C, Sgonc R, Bφck G, Dierich MP, et al. Effect of neopterin and 7,8-dihydroneopterin on tumor necrosis factor alpha induced programmed cell death. FEBS Lett 1995;364:234-8.   Back to cited text no. 16    
17.Laroux FS, Pavlick KP, Hines IN, Kawachi HS, Harada, Bharwani S, et al. Role of nitric oxide in inflammation. Acta Physiol Scand 2001;173:113-8.   Back to cited text no. 17    
18.Winder B, Sepp N, Kowald E, Ortner U, Wirleitner B, Fritsch P, et al. Enhanced tryptophan degradation in systemic lupus erythematosus. Immunobiology 1999 2000;201:621-30.  Back to cited text no. 18    
19.Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 1998;281:1191-3.  Back to cited text no. 19  [PUBMED]  [FULLTEXT]
20.Khakoo S, Glue P, Grellier L, Wells B, Bell A, Dash C, et al. Ribavirin and interferon alfa -2b in chronic hepatitis C: Assessment of possible pharmocikinetic and pharmocodynamic interaction. Br J Clin Pharmacol 1998;46:563-70.  Back to cited text no. 20  [PUBMED]  [FULLTEXT]
21.Costa CA, Trivelato GC, Pinto AM, Bechara. Correlation between plasma 5-aminolevalunic acid concentrations and indicators of oxidative stress in lead-exposed workers. Clin Chem 1997;43:1196-202.  Back to cited text no. 21    
22.Engin AB, Tuzun D, Sahin G. Evaluation of pteridine metabolism in battery workers chronically exposed to lead. Hum Exp Toxicol 2006;25:353-9.   Back to cited text no. 22  [PUBMED]  [FULLTEXT]
23.Fuchs D, Hausen A, Reibnegger G, Werne ER, Dierich MP, Wachter H. Neopterin as a marker for cell mediated immunity: Application in HIV infection. Immunol Today 1988;9:150-5.   Back to cited text no. 23    
24.Fuchs D, Weiss G, Wachter H. The role of neopterin as a monitor of cellular immune activation in transplantation, inflammatory, infectious and malignant diseases. Crit Rev Clin Lab Sci 1992;29:307-41.   Back to cited text no. 24  [PUBMED]  
25.Dukes CS, Matthews TJ, Rivadeneira ED, Weinberg JB. Neopterin production by HIV-1-infected mononuclear phagocytes. J Leuk Biol 1994;56:650-3.   Back to cited text no. 25    
26.Prakova G, Gidikova P, Slavov E, Sandeva G, Stanilova S. The Potential role of neopterin as a biomarker for silicosis. Trakia Journal of Sciences 2005; 3: 37-41.   Back to cited text no. 26    
27.Kullich W. Correlation of interleukin-2 receptor and neopterin secretion in rheumatoid arthritis. Clin Rheumatol 1993;12:387-91.  Back to cited text no. 27  [PUBMED]  
28.Zeuzem S, Feinman SV, Rasenack J, Heathcote EJ, Lai MY, Gane E, et al. Peginterferon alfa-2a in patients with chronic hepatitis C. N Engl J Med 2000;343:1666-72.  Back to cited text no. 28  [PUBMED]  [FULLTEXT]
29.Santelli G, Mellio G, Marfella A, Napolitano MD, Alesio V, Satriano RA, et al. Urinary neopterin and immunological feature in patient with kaposi's Sarcoma. Eur J Cancer Clin Oncol 1998;24:1391-6.  Back to cited text no. 29    
30.Zengping W, Minyue D, Hongnu C, Jing H. The Increased serum levels of neopterin and soluble Interleukin-2 receptor in Intrahepatic cholestasis of pregnancy. Acta Obstet Gyneocol Scand 2004;83:1067.   Back to cited text no. 30    
31.Mabrouk G, EI-Edel R, Ahmed Rabie El. Soluble interleukin-2 receptor alpha(sIL2Rα) and neopterin in patient with pulmonary tuberculosis. Available from: http://eji. egyptscience.com/previous/pro2002/pro2002-7,htm. October 9, 2008.  Back to cited text no. 31    
32.Fuith LC, Fuchs D, Hausen A, Hetzel H, Reibnegger G, Werner ER, et al. Neopterin: A marker of cell-mediated immune activation in human pregnancy. Int J Fertil 1991;36:372-5.  Back to cited text no. 32    
33.Yao YM, Yu Y, Wang YP, Tian HM, Sheng ZY. Elevation serum neopterin level: Its relation to endotoxaemia and sepsis in patient with major burns. Eur J Clin Investig 1996;26:224.  Back to cited text no. 33    
34.Razumovitch JA, Semenkova GN, Fuchs D, Cherenkevich SN. Influence of neopterin on the generation of reactive oxygen species in human neutrophils. FEBS Lett 2003;549:83-6.  Back to cited text no. 34  [PUBMED]  [FULLTEXT]
35.Werner ER, Bichler A, Daxenbichler G, Fuchs D, Fuith LC, Hausen A, et al. Determination of Neopterin in serum and urine. Clin Chem 1987;33:62-6.   Back to cited text no. 35  [PUBMED]  [FULLTEXT]
36.Wilmer A, Nolchen B, Tilg H, Herold M, Pechlaner C, Judmaier G, et al. Serum Neopterin concentrations in chronic liver disease. Gut 1995;31:108-12.   Back to cited text no. 36    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1]


This article has been cited by
1 Strontium Chloride: Can It Be a New Treatment Option for Ulcerative Colitis?
Firdevs Topal,Ozlem Yonem,Nevin Tuzcu,Mehmet Tuzcu,Hilmi Ataseven,Melih Akyol
BioMed Research International. 2014; 2014: 1
[Pubmed]
2 Interferon-?-induced inflammatory markers and the risk of cancer: The Hordaland Health Study
Hui Zuo,Grethe S. Tell,Stein E. Vollset,Per M. Ueland,Ottar Nygård,Øivind Midttun,Klaus Meyer,Arve Ulvik,Simone J.P.M. Eussen
Cancer. 2014; : n/a
[Pubmed]
3 A Pilot Study on Neopterin Levels and Tryptophan Degradation in Zinc-Exposed Galvanization Workers
Elif Seyda Sarac,Gözde Girgin,S.Sezin Palabiyik,Mohammad Charehsaz,Ahmet Aydin,Gönül Sahin,Terken Baydar
Biological Trace Element Research. 2013; 151(3): 330
[Pubmed]
4 Applications of quantitative serum neopterin determination in dogs affected by leishmaniasis-preliminary study
Matteo, C. and Daniele, S. and Fulvio, L. and Francesca, B. and Carlotta, M. and Silvia, P. and Vincenzo, C. and Andrea, S. and Beniamino, T.
Journal of Animal and Veterinary Advances. 2012; 11(21): 3937-3942
[Pubmed]
5 Neopterin in patients with chronic kidney disease and patients with coronary artery disease
Formanowicz, D.
Biotechnologia. 2012; 93(1): 59-67
[Pubmed]
6 Blunted epidermal L-tryptophan metabolism in vitiligo affects immune response and ROS scavenging by Fenton chemistry, Part 2: Epidermal H 2O2/ONOO--mediated stress in vitiligo hampers indoleamine 2,3-dioxygenase and aryl hydrocarbon receptor-mediated immune response signaling
Schallreuter, K.U. and Salem, M.A.E.L. and Gibbons, N.C.J. and Maitland, D.J. and Marsch, E. and Elwary, S.M.A. and Healey, A.R.
FASEB Journal. 2012; 26(6): 2471-2485
[Pubmed]
7 Serum neopterin estimation as an indicator for safe blood transfusion
Shameem Banu, A.S. and Latha, P. and Kaveri, K. and Jayakumar, S.
Journal of Clinical and Diagnostic Research. 2011; 5(8): 1555-1558
[Pubmed]
8 Changes of cytokine production and cell viability of peripheral blood mononuclear cells from silicosis patients: Effect of in vitro treatment with acetylsalicylic acid
Dobreva, Z.G., Prakova, G.R., Slavov, E.S., Stanilova, S.A.
Toxicology and Industrial Health. 2010; 26(1): 3-9
[Pubmed]



 

Top
Print this article  Email this article
Previous article Next article