Skip to main content
NCBI home page
Thorax logoLink to Thorax
. 1999 Dec;54(12):1093–1098. doi: 10.1136/thx.54.12.1093

Fas and Fas ligand expression in cystic fibrosis airway epithelium

I Durieu 1, C Amsellem 1, C Paulin 1, M Chambe 1, J Bienvenu 1, G Bellon 1, Y Pacheco 1
PMCID: PMC1763765  PMID: 10567629

Abstract

BACKGROUND—Cystic fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and defective expression of CFTR protein in epithelial cells. The main cause of mortality in CF is linked to chronic inflammatory and infectious airway processes. Recent studies have suggested perturbations in the apoptotic process in CF cell lines and enterocytes. A study was undertaken to investigate the expression of Fas and Fas ligand (FasL) in CF bronchial epithelium and CF tracheal cell lines.
METHODS—Immunohistochemical staining for Fas (alkaline phosphatase anti-alkaline phosphatase) and FasL (immunoperoxidase) was performed in eight CF bronchial epithelial samples and four controls and immunohistochemical DNA fragmentation (TUNEL) was carried out in four CF patients and four controls. Immunofluorescence staining and flow cytometric analysis of Fas and FasL expression was performed in two human tracheal epithelial cell lines (HTEC) with normal and CF genotype. The dosage of serum soluble FasL was examined in 21 patients with CF and 14 healthy volunteers.
RESULTS—FasL expression was markedly increased in patients with CF in both the ciliated and submucosal glandular bronchial epithelium compared with controls; Fas was similarly expressed in bronchial samples from controls and CF patients in both the ciliated epithelium and submucosal glands. High levels of DNA fragmentation were observed in CF but with some epithelial cell alterations. Serum concentrations of soluble FasL were frequently undetectable in patients with CF. In vitro, HTEC expressed Fas and FasL in both genotypes. A higher mean fluorescence intensity for FasL expression was noted in CF genotype HTEC with median (range) for six experiments of 74 (25-101) for CF cells and 42 (21-70) for non-CF cells.
CONCLUSION—Fas/FasL interaction is probably implicated in the human CF airway apoptotic pathway. The mechanisms of induction of FasL expression and its role in inducing tissue damage or remodelling or in controlling local inflammatory cell apoptosis remain to be determined.



Full Text

The Full Text of this article is available as a PDF (11.6 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Buttke T. M., Sandstrom P. A. Oxidative stress as a mediator of apoptosis. Immunol Today. 1994 Jan;15(1):7–10. doi: 10.1016/0167-5699(94)90018-3. [DOI] [PubMed] [Google Scholar]
  2. CHERNICK W. S., BARBERO G. J. Composition of tracheobronchial secretions in cystic fibrosis of the pancreas and bronchiectasis. Pediatrics. 1959 Nov;24:739–745. [PubMed] [Google Scholar]
  3. Chen J. J., Sun Y., Nabel G. J. Regulation of the proinflammatory effects of Fas ligand (CD95L). Science. 1998 Nov 27;282(5394):1714–1717. doi: 10.1126/science.282.5394.1714. [DOI] [PubMed] [Google Scholar]
  4. DiMango E., Ratner A. J., Bryan R., Tabibi S., Prince A. Activation of NF-kappaB by adherent Pseudomonas aeruginosa in normal and cystic fibrosis respiratory epithelial cells. J Clin Invest. 1998 Jun 1;101(11):2598–2605. doi: 10.1172/JCI2865. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Druilhe A., Wallaert B., Tsicopoulos A., Lapa e Silva J. R., Tillie-Leblond I., Tonnel A. B., Pretolani M. Apoptosis, proliferation, and expression of Bcl-2, Fas, and Fas ligand in bronchial biopsies from asthmatics. Am J Respir Cell Mol Biol. 1998 Nov;19(5):747–757. doi: 10.1165/ajrcmb.19.5.3166. [DOI] [PubMed] [Google Scholar]
  6. Durieu I., Peyrol S., Gindre D., Bellon G., Durand D. V., Pacheco Y. Subepithelial fibrosis and degradation of the bronchial extracellular matrix in cystic fibrosis. Am J Respir Crit Care Med. 1998 Aug;158(2):580–588. doi: 10.1164/ajrccm.158.2.9707126. [DOI] [PubMed] [Google Scholar]
  7. Fine A., Miranda K., Farmer S. R., Anderson N. L. Effect of insoluble extracellular matrix molecules on Fas expression in epithelial cells. J Cell Physiol. 1998 Mar;174(3):285–292. doi: 10.1002/(SICI)1097-4652(199803)174:3<285::AID-JCP2>3.0.CO;2-K. [DOI] [PubMed] [Google Scholar]
  8. Goldman M. J., Anderson G. M., Stolzenberg E. D., Kari U. P., Zasloff M., Wilson J. M. Human beta-defensin-1 is a salt-sensitive antibiotic in lung that is inactivated in cystic fibrosis. Cell. 1997 Feb 21;88(4):553–560. doi: 10.1016/s0092-8674(00)81895-4. [DOI] [PubMed] [Google Scholar]
  9. Gottlieb R. A., Dosanjh A. Mutant cystic fibrosis transmembrane conductance regulator inhibits acidification and apoptosis in C127 cells: possible relevance to cystic fibrosis. Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3587–3591. doi: 10.1073/pnas.93.8.3587. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Griffith T. S., Brunner T., Fletcher S. M., Green D. R., Ferguson T. A. Fas ligand-induced apoptosis as a mechanism of immune privilege. Science. 1995 Nov 17;270(5239):1189–1192. doi: 10.1126/science.270.5239.1189. [DOI] [PubMed] [Google Scholar]
  11. Hamann K. J., Dorscheid D. R., Ko F. D., Conforti A. E., Sperling A. I., Rabe K. F., White S. R. Expression of Fas (CD95) and FasL (CD95L) in human airway epithelium. Am J Respir Cell Mol Biol. 1998 Oct;19(4):537–542. doi: 10.1165/ajrcmb.19.4.3100. [DOI] [PubMed] [Google Scholar]
  12. Hsieh S. C., Huang M. H., Tsai C. Y., Tsai Y. Y., Tsai S. T., Sun K. H., Yu H. S., Han S. H., Yu C. L. The expression of genes modulating programmed cell death in normal human polymorphonuclear neutrophils. Biochem Biophys Res Commun. 1997 Apr 28;233(3):700–706. doi: 10.1006/bbrc.1997.6529. [DOI] [PubMed] [Google Scholar]
  13. Kasibhatla S., Brunner T., Genestier L., Echeverri F., Mahboubi A., Green D. R. DNA damaging agents induce expression of Fas ligand and subsequent apoptosis in T lymphocytes via the activation of NF-kappa B and AP-1. Mol Cell. 1998 Mar;1(4):543–551. doi: 10.1016/s1097-2765(00)80054-4. [DOI] [PubMed] [Google Scholar]
  14. Khan T. Z., Wagener J. S., Bost T., Martinez J., Accurso F. J., Riches D. W. Early pulmonary inflammation in infants with cystic fibrosis. Am J Respir Crit Care Med. 1995 Apr;151(4):1075–1082. doi: 10.1164/ajrccm/151.4.1075. [DOI] [PubMed] [Google Scholar]
  15. Kong L., Ogawa N., Nakabayashi T., Liu G. T., D'Souza E., McGuff H. S., Guerrero D., Talal N., Dang H. Fas and Fas ligand expression in the salivary glands of patients with primary Sjögren's syndrome. Arthritis Rheum. 1997 Jan;40(1):87–97. doi: 10.1002/art.1780400113. [DOI] [PubMed] [Google Scholar]
  16. Leithäuser F., Dhein J., Mechtersheimer G., Koretz K., Brüderlein S., Henne C., Schmidt A., Debatin K. M., Krammer P. H., Möller P. Constitutive and induced expression of APO-1, a new member of the nerve growth factor/tumor necrosis factor receptor superfamily, in normal and neoplastic cells. Lab Invest. 1993 Oct;69(4):415–429. [PubMed] [Google Scholar]
  17. Lemnaouar M., Chastre E., Paul A., Mergey M., Veissière D., Cherqui G., Barbry P., Simon-Bouy B., Fanen P., Gespach C. Oncogene-mediated propagation of tracheal epithelial cells from two cystic fibrosis fetuses with different mutations. Characterization of CFT-1 and CFT-2 cells in culture. Eur J Clin Invest. 1993 Mar;23(3):151–160. doi: 10.1111/j.1365-2362.1993.tb00754.x. [DOI] [PubMed] [Google Scholar]
  18. Maiuri L., Raia V., De Marco G., Coletta S., de Ritis G., Londei M., Auricchio S. DNA fragmentation is a feature of cystic fibrosis epithelial cells: a disease with inappropriate apoptosis? FEBS Lett. 1997 May 19;408(2):225–231. doi: 10.1016/s0014-5793(97)00347-5. [DOI] [PubMed] [Google Scholar]
  19. Meredith J. E., Jr, Fazeli B., Schwartz M. A. The extracellular matrix as a cell survival factor. Mol Biol Cell. 1993 Sep;4(9):953–961. doi: 10.1091/mbc.4.9.953. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Midis G. P., Shen Y., Owen-Schaub L. B. Elevated soluble Fas (sFas) levels in nonhematopoietic human malignancy. Cancer Res. 1996 Sep 1;56(17):3870–3874. [PubMed] [Google Scholar]
  21. Mitsiades N., Poulaki V., Kotoula V., Mastorakos G., Tseleni-Balafouta S., Koutras D. A., Tsokos M. Fas/Fas ligand up-regulation and Bcl-2 down-regulation may be significant in the pathogenesis of Hashimoto's thyroiditis. J Clin Endocrinol Metab. 1998 Jun;83(6):2199–2203. doi: 10.1210/jcem.83.6.4853. [DOI] [PubMed] [Google Scholar]
  22. Nagata S., Golstein P. The Fas death factor. Science. 1995 Mar 10;267(5203):1449–1456. doi: 10.1126/science.7533326. [DOI] [PubMed] [Google Scholar]
  23. Niehans G. A., Brunner T., Frizelle S. P., Liston J. C., Salerno C. T., Knapp D. J., Green D. R., Kratzke R. A. Human lung carcinomas express Fas ligand. Cancer Res. 1997 Mar 15;57(6):1007–1012. [PubMed] [Google Scholar]
  24. Ogrinc G., Kampalath B., Tomashefski J. F., Jr Destruction and loss of bronchial cartilage in cystic fibrosis. Hum Pathol. 1998 Jan;29(1):65–73. doi: 10.1016/s0046-8177(98)90392-6. [DOI] [PubMed] [Google Scholar]
  25. Rahman I., MacNee W. Role of transcription factors in inflammatory lung diseases. Thorax. 1998 Jul;53(7):601–612. doi: 10.1136/thx.53.7.601. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Riordan J. R., Rommens J. M., Kerem B., Alon N., Rozmahel R., Grzelczak Z., Zielenski J., Lok S., Plavsic N., Chou J. L. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989 Sep 8;245(4922):1066–1073. doi: 10.1126/science.2475911. [DOI] [PubMed] [Google Scholar]
  27. Schneider P., Holler N., Bodmer J. L., Hahne M., Frei K., Fontana A., Tschopp J. Conversion of membrane-bound Fas(CD95) ligand to its soluble form is associated with downregulation of its proapoptotic activity and loss of liver toxicity. J Exp Med. 1998 Apr 20;187(8):1205–1213. doi: 10.1084/jem.187.8.1205. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Shah P. L., Scott S. F., Knight R. A., Marriott C., Ranasinha C., Hodson M. E. In vivo effects of recombinant human DNase I on sputum in patients with cystic fibrosis. Thorax. 1996 Feb;51(2):119–125. doi: 10.1136/thx.51.2.119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Suda T., Hashimoto H., Tanaka M., Ochi T., Nagata S. Membrane Fas ligand kills human peripheral blood T lymphocytes, and soluble Fas ligand blocks the killing. J Exp Med. 1997 Dec 15;186(12):2045–2050. doi: 10.1084/jem.186.12.2045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Suda T., Nagata S. Purification and characterization of the Fas-ligand that induces apoptosis. J Exp Med. 1994 Mar 1;179(3):873–879. doi: 10.1084/jem.179.3.873. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Tabary O., Zahm J. M., Hinnrasky J., Couetil J. P., Cornillet P., Guenounou M., Gaillard D., Puchelle E., Jacquot J. Selective up-regulation of chemokine IL-8 expression in cystic fibrosis bronchial gland cells in vivo and in vitro. Am J Pathol. 1998 Sep;153(3):921–930. doi: 10.1016/S0002-9440(10)65633-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Tanaka M., Suda T., Haze K., Nakamura N., Sato K., Kimura F., Motoyoshi K., Mizuki M., Tagawa S., Ohga S. Fas ligand in human serum. Nat Med. 1996 Mar;2(3):317–322. doi: 10.1038/nm0396-317. [DOI] [PubMed] [Google Scholar]
  33. Taïeb J., Mathurin P., Poynard T., Gougerot-Pocidalo M. A., Chollet-Martin S. Raised plasma soluble Fas and Fas-ligand in alcoholic liver disease. Lancet. 1998 Jun 27;351(9120):1930–1931. doi: 10.1016/S0140-6736(05)78614-1. [DOI] [PubMed] [Google Scholar]
  34. Zahm J. M., Gaillard D., Dupuit F., Hinnrasky J., Porteous D., Dorin J. R., Puchelle E. Early alterations in airway mucociliary clearance and inflammation of the lamina propria in CF mice. Am J Physiol. 1997 Mar;272(3 Pt 1):C853–C859. doi: 10.1152/ajpcell.1997.272.3.C853. [DOI] [PubMed] [Google Scholar]

Articles from Thorax are provided here courtesy of BMJ Publishing Group

RESOURCES