Cytokine polymorphisms in silicosis and other pneumoconiosis

  • Berran Yucesoy
  • Val vallyathan
  • Douglas P. Landsittel
  • Petia Simeonova
  • Michael I. Luster
Part of the Developments in Molecular and Cellular Biochemistry book series (DMCB, volume 37)


Silicosis and coal workers’ pneumoconiosis are complex multifactorial lung diseases whose etiopathogenesis are not well defined. It is generally accepted that fibrotic lung disorders are mediated by macrophage-derived cytokines and growth factors. There is evidence showing a crucial role for tumor necrosis factor-a (TNF-a) and interleukin-1 (IL-1) in inflammation caused by silica dust and in the transition from simple to progressive massive fibrosis. In this review we discuss genetic polymorphisms responsible for regulating the production of these proinflammatory cytokines and their role in modifying silicosis severity. (Mol Cell Biochem 234/235: 219–224, 2002)

Key words

silicosis pneumoconiosis cytokines polymorphism TNF-a 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Wagner GR: Asbestosis and silicosis. Lancet 349: 1311–1315, 1997PubMedCrossRefGoogle Scholar
  2. 2.
    NIOSH: NIOSH alert: Request for assistance in preventing silicosis and deaths from sandblasting. Cincinnati: US Department of Health and Human Services, Public Health Service, CDC, NIOSH, DHHS publication no. (NIOSH)92–102, 1992Google Scholar
  3. 3.
    Legal and Medical Resource Center for Silicosis Victims; last modified January 23, 2002
  4. 4.
    Lim Y, Kim JH, Kim KA, Chang HS, Park YM, Ahn BY, Phee YG: Silica-induced apoptosis in vitro and in vivo. Toxicol Lett 108: 335339, 1999PubMedCrossRefGoogle Scholar
  5. 5.
    Castranova V, Vallyathan V: Silicosis and coal workers’ pneumoconiosis. Environ Health Perspect 108: 675–684, 2000PubMedGoogle Scholar
  6. 6.
    Kelley J: Cytokines of the lung. Am Rev Respir Dis 141: 765–788, 1990PubMedCrossRefGoogle Scholar
  7. 7.
    Gauldie J, Jordana M, Gerard Cox: Cytokines and pulmonary fibrosis. Thorax 48: 931–935, 1993PubMedCrossRefGoogle Scholar
  8. 8.
    Vaillant P, Menard O, Vignaud JM, Martinet N, Martinet Y: The role of cytokines in human lung fibrosis. Monaldi Arch Chest Dis 51: 145152, 1996PubMedGoogle Scholar
  9. 9.
    Ward PA, Hunninghake GW: Lung inflammation and fibrosis. Am J Respir Crit Care Med 157: 123–129, 1998Google Scholar
  10. 10.
    Struhar DJ, Harbeck RJ, Gegen N, Kawada H, Mason RJ: Increased expression of class II antigen of the major histocompatibility complex on alveolar macrophages and alveolar type II cells and interleukin-1 (IL-1) secretion from alveolar macrophages in an animal model of silicosis. Clin Exp Immunol 77: 281–284, 1989PubMedGoogle Scholar
  11. 11.
    Driscoll KE, Lindenschmidt RC, Maurer JK, Higgins JM, Ridder G: Pulmonary response to silica or titanium-dioxide: Inflammatory cells, alveolar macrophage-derived cytokines, and histopathology. Am J Respir Cell Mol Biol 2: 381–390, 1990PubMedGoogle Scholar
  12. 12.
    Mohr C, Gemsa D, Graebner C, Hemenway DR, Leslie KO, Absher PM, Davis GS: Systemic macrophage stimulation in rats with silicosis: Enhanced release of tumour necrosis factor-a from alveolar and peritoneal macrophages. Am J Respir Cell Mol Biol 5: 395–402, 1991PubMedGoogle Scholar
  13. 13.
    Davis GS, Pfeiffer LM, Hemenway DR: Persistent overexpression of interleukin-lbeta and tumour necrosis factor-alpha in murine silicosis. J Environ Pathol Toxicol Oncol 17: 99–114, 1998PubMedGoogle Scholar
  14. 14.
    Orfila C, Lepert JC, Gossart S, Frisach MF, Cambon C, Pipy B: Immunocytochemical characterization of lung macrophage surface phenotypes and expression of cytokines in acute experimental silicosis in mice. Histochem J 30: 857–67, 1998PubMedCrossRefGoogle Scholar
  15. 15.
    Piguet PF, Collart MA, Grau GE, Sappino A, Vassalli P: Requirement of tumor necrosis factor for development of silica-induced pulmonary fibrosis. Nature 344: 245–247, 1990PubMedCrossRefGoogle Scholar
  16. 16.
    Gossart S, Cambon C, Orfila C, Seguelas MH, Lepert JC: Reactive oxygen intermediates as regulators of TNF-a production in rat lung inflammation induced by silica. J Immunol 156: 1540–1548, 1996PubMedGoogle Scholar
  17. 17.
    Schmidt JA, Oliver CN, Lepe-Zuniga JL, Green I, Gery I: Silica-stimulated monocytes release fibroblast proliferation factors identical to interleukin I. A potential role for interleukin 1 in the pathogenesis of silicosis. J Clin Invest 73: 1462–1472, 1984PubMedCrossRefGoogle Scholar
  18. 18.
    Savici D, He B, Geist LJ, Monick MM, Hunninghake GW: Silica increases tumor necrosis factor (TNF) production, in part, by upregulating the TNF promoter. Exp Lung Res 20: 613–625, 1994PubMedCrossRefGoogle Scholar
  19. 19.
    Borin PJA, Palmen N, Engelen JJM, Buurman WA: Spontaneous and stimulated release of tumor necrosis factor-alpha (TNF) from blood monocytes of miners with coal workers pneumoconiosis. Am Rev Respir Dis 138: 1589–1594, 1988Google Scholar
  20. 20.
    Schins RP, Borm PJ: Epidemiological evaluation of monocyte TNFalpha as an exposure and effect marker in pneumoconiosis: A five year follow up study of coal workers. Occup Environ Med 52: 441–450, 1995PubMedCrossRefGoogle Scholar
  21. 21.
    Kim KA, Lim Y, Kim JH, Kim EK, Chang HS, Park YM, Ahn BY: Potential biomarker of coal workers’ pneumoconiosis. Eur Respir J 8: 834–842, 1995CrossRefGoogle Scholar
  22. 22.
    Lasalle P, Gosset P, Aerts C, Fournier E, Lafitte JE, Degreef JM, Wallaert B, Tonnel AB, Voisin C: Abnormal secretion of interleukin-1 and tumor necrosis factor-a by alveolar macrophages in coal workers’ pneumoconiosis: Comparison between simple pneumoconiosis and progressive massive fibrosis. Exp Lung Res 16: 73–80, 1990CrossRefGoogle Scholar
  23. 23.
    Vanhee D, Gosset P, Boitelle A, Wallaert B, Tonnel AB: Cytokines and cytokine network in silicosis and coal workers’ pneumoconiosis. Eur Respir J 8: 834–842, 1995PubMedGoogle Scholar
  24. 24.
    Katsnelson BA, Polzik EV, Privalova LI: Some aspects of the problem of individual predisposition to silicosis. Environ Health Perspect 68: 175–185, 1986PubMedCrossRefGoogle Scholar
  25. 25.
    Kornman KS, Crane A, Wang H-Y, di Giovine FS, Newman MG, Pirk FW, Wilson TG, Higginbottom FL, Duff GW: The interleukin-1 genotype as a severity factor in adult periodontal disease. J Clin Periodontol 24: 72–77, 1997PubMedCrossRefGoogle Scholar
  26. 26.
    Pociot F, Molvig J, Wogensen L, Worsaae H, Nerup J: A TaqI polymorphism in the human interleukin-113 (IL-lß gene correlates with IL-13 secretion in vitro. Eur J Clin Invest 22: 396–402, 1992PubMedCrossRefGoogle Scholar
  27. 27.
    Danis VA, Millington M, Hyland VJ, Grennan D: Cytokine production by normal monocytes: Inter-subject variation and relationship to an IL-1 receptor antagonist (IL-1Ra) gene polymorphism. Clin Exp Immunol 99: 303–310, 1995PubMedCrossRefGoogle Scholar
  28. 28.
    Perrey C, Pravica V, Sinnott PJ, Hutchinson IV: Genotyping for polymorphisms in interferon-y, interleukin-10, transforming growth factor-3 1 and tumour necrosis factor-a genes: Atechnical report. Trans Immunol 6: 193–197, 1998CrossRefGoogle Scholar
  29. 29.
    Carrot MC, Katzman P, Alicot EM, Koller BH, Geraghty DE, Orr HT, Strominger JL, Spies T: Linkage map of the human major histocompatibility complex including the tumor necrosis factor genes. Proc Natl Acad Sci USA 84: 8535–8539, 1987CrossRefGoogle Scholar
  30. 30.
    Wilson AG, de Vries N, Pociot F, di Giovine FS, van der Potte LB, Duff GW: An allelic polymorphism within the human tumor necrosis factor alpha promoter region is strongly associated with HLAA1, B8, and D3 alleles. J Exp Med 177: 557–560, 1993PubMedCrossRefGoogle Scholar
  31. 31.
    D’Alfonso S, Richiardi PM: A polymorphic variation in a putative regulation box of the TNF-a promoter region. Immunogenetics 3: 150–154, 1994Google Scholar
  32. 32.
    McGuire W, Hill AV S, Allsopp CEM, Greenwood BM, Kwiatkowski D: Variation in the TNF-a promoter region associated with susceptibility to cerebral malaria. Nature 371: 508–511, 1994PubMedCrossRefGoogle Scholar
  33. 33.
    Cabrera M, Shaw MA, Sharples C, Williams H, Castes M, Convit J, Blackwell JM: Polymorphism in tumor necrosis factor genes associated with mucocutaneous leishmaniasis. J Exp Med 182: 1259–1264, 1995PubMedCrossRefGoogle Scholar
  34. 34.
    McManus R, Wilson AG, Mansfield J, Weir DG, Duff GW, Kelleher D: TNF2, a polymorphism of the tumour necrosis-a gene promoter, is a component of the celiac disease major histocompatibility complex haplotype. Eur J Immunol 26: 2113–2118, 1996PubMedCrossRefGoogle Scholar
  35. 35.
    Huang S-L, Su C-H, Chang S-C: Tumor necrosis factor-a gene polymorphism in chronic bronchitis. Am J Respir Crit Care Med 156: 14361439, 1997Google Scholar
  36. 36.
    Arias AI, Giles B, Eiermann TH, Sterry W, Pandey JP: Tumor necrosis factor-alpha gene polymorphism in psoriasis. Exp Clin Immunogenet 14: 118–122, 1997PubMedGoogle Scholar
  37. 37.
    Sullivan KE, Wooten C, Schmeckpeper Goldman D, Petri MA: A promoter polymorphism of tumor necrosis factor-a associated with systemic lupus erythematosus in African-Americans. Arthritis Rheum 40: 2207–2211, 1997PubMedCrossRefGoogle Scholar
  38. 38.
    Zhai R, Jetten M, Schins RPF, Franssen H, Borm PJA: Polymorphisms in the promoter of the tumor necrosis factor-a gene in coal miners. Am J Indust Med 34: 318–324 1998CrossRefGoogle Scholar
  39. 39.
    Pociot F, Briant L, Jongeneel CV, Molvig J, Worsaae H, Abbal M, Thomsen M, Nerup J, Cambon-Thomsen A: Association of tumor necrosis factor (TNF) and class II major histocompatibility complex alleles with the secretion of TNF-a and TNF-p by human mononuclear cells: A possible link to insulin-dependent diabetes mellitus. Eur J Immunol 23: 224–231, 1993PubMedCrossRefGoogle Scholar
  40. 40.
    Jacob CO, Fronek Z, Lewis GD, Koo M, Hansen JA, McDevitt HO: Heritable major histocompatibilty complex classll-associated differences in production of tumor necrosis factor-a: Relevance to genetic predisposition to systemic lupus erythematosus. Proc Natl Acad Sci USA 87: 1233–1237, 1990PubMedCrossRefGoogle Scholar
  41. 41.
    Kroeger KM, Carville KS, Abraham LJ: The —308 tumor necrosis factor-a promoter polymorphism effects transcription. Mol Immunol 34: 391–399,1997PubMedCrossRefGoogle Scholar
  42. 42.
    Roux-Lombard P: The interleukin-1 family. Eur Cytokine Netw 9: 565576, 1998PubMedGoogle Scholar
  43. 43.
    Blakemore AIF, Tarlow JK, Cork MJ, Gordon C, Emery P, Duff GW: Interleukin-I receptor antagonist gene polymorphism as a disease severity factor in systemic lupus erythematosus. Arth Rheum 37: 13801385, 1994Google Scholar
  44. 44.
    Mansfield JC, Holden H, Tarlow JK, di Giovine FS, McDowell TL, Wilson AG, Holdsworth CD, Duff GW: Novel genetic association between ulcerative colitis and the anti-inflammmatory cytokine interleukin1 receptor antagonist. Gastroenterology 106: 637–642, 1994PubMedGoogle Scholar
  45. 45.
    Clay FE, Cork MJ, Tarlow JK, Blakemore AIF, Harrington CI, Lewis F, Duff GW: Interleukin 1 receptor antagonist gene polymorphism association with lichen sclerosis. Hum Genet 94: 407–410, 1994PubMedCrossRefGoogle Scholar
  46. 46.
    Tarlow JK, Clay FE, Cork MJ, Blakemore AIF, McDonagh AJG, Messenger AG, Duff GW: Severity of alopecia areata is associated with a polymorphism in the interleukin-1 receptor antagonist gene. J Invest Dermatol 103: 387–390, 1994PubMedCrossRefGoogle Scholar
  47. 47.
    McDowell TL, Symons JA, Ploski R, Forre O, Duff GW: A genetic association between juvenile rheumatoid arthritis and a novel interleukinla polymorphism. Arthritis Rheum 38: 221–228, 1995PubMedCrossRefGoogle Scholar
  48. 48.
    Jouvenne P, ChaudharyA, Buchs N, di Giovine FS, Duff GW, Miossec P: Possible genetic association between interleukin-la gene polymorphism and the severity of chronic polyarthritis. Eur Cytokine Netw 10: 33–36, 1999PubMedGoogle Scholar
  49. 49.
    Di Giovine FS, Cork MJ, Crane A, Mee JB, Duff GW: Novel genetic association of an IL-10 gene variation at+3953 with IL-1 ß protein production and psoriasis. Cytokine 7: 606, 1995Google Scholar
  50. 50.
    Gualde N, De Leobardy J, Serizay B, Malinvaud O: HL-A and silicosis. Am Rev Respir Dis 116: 334–336, 1977PubMedGoogle Scholar
  51. 51.
    Koskinen H, Tiilikainen A, Nordman H: Increased prevalence of HLAAw19 and the phenogroup Awl9, B18 in advanced silicosis. Chest 83: 848–852, 1983PubMedCrossRefGoogle Scholar
  52. 52.
    Honda K, Kimura A, Dong R-P, Tamai H, Nagato H, Nishimura Y, Sasazuki T: Immunogenetic analysis of silicosis in Japan. Am J Respir Cell Mol Biol 8: 106–111, 1993PubMedGoogle Scholar
  53. 53.
    Rihs HP, Lipps P, May-Taube K, Jager D, Schmidt EW, Hegemann JH, Baur X: Immunogenetic studies on HLA-DR in German coal miners with and without coal workers’ pneumoconiosis. Lung 172: 347–354, 1994PubMedCrossRefGoogle Scholar
  54. 54.
    Wordsworth P, Bell J: Polygenic susceptibility in rheumatoid arthritis. Ann Rheum Dis 50: 343–346, 1991PubMedCrossRefGoogle Scholar
  55. 55.
    Yucesoy B, Vallyathan V, Landsittel DP, Sharp DS, Weston A, Burleson G, Simeonova PP, McKinstry M, Luster MI: Association of TNF-a and IL-1 gene polymorphisms with silicosis. ToxicolAppl Pharmacol 172: 75–82, 2001Google Scholar
  56. 56.
    Yucesoy B, Vallyathan V, Landsittel DP, Sharp DS, Matheson JM, Burleson F, Luster MI: Polymorphisms of the IL-1 gene complex in coal miners with silicosis. Am J Ind Med 39: 286–291, 2001PubMedCrossRefGoogle Scholar
  57. 57.
    Casini-Raggi V, Kam L, Chong YJT, Fiocchi C, Pizarro TT, Cominelli F: Mucosal imbalance of IL-1 and IL-1 receptor antagonist in inflammatory bowel disease. A novel mechanism of chronic intestinal inflammation. J Immunol 154: 2434–2440, 1995PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Berran Yucesoy
    • 1
  • Val vallyathan
    • 2
  • Douglas P. Landsittel
    • 3
  • Petia Simeonova
    • 4
  • Michael I. Luster
    • 4
  1. 1.Ankara UniversityFaculty of Pharmacy, Department of ToxicologyAnkaraTurkey
  2. 2.Pathology and Physiology Research BranchMorgantown
  3. 3.Biostatistics BranchMorgantown
  4. 4.Toxicology and Molecular Biology BranchHealth Effects and Laboratory Division, National Institute for Occupational Safety and HealthMorgantownUSA

Personalised recommendations