Skip to main content
PMC home page
Journal of Cellular and Molecular Medicine logoLink to Journal of Cellular and Molecular Medicine
. 2007 May 1;8(3):285–293. doi: 10.1111/j.1582-4934.2004.tb00318.x

The central role of Fas‐ligand cell signaling in inflammatory lung diseases

G A DosReis 1,✉, Valeria M Borges 2, W A Zin 1
PMCID: PMC6740074  PMID: 15491504

Abstract

Following inflammation and injury in the lung, loss of epithelial cell precursors could determine the balance between tissue regeneration and fibrosis. This review discusses evidence that proapoptotic Fas‐Fas ligand (FasL) signaling plays a central role in pulmonary inflammation, injury and fibrosis. FasL signaling induces inflammatory apoptosis in epithelial cells and alveolar macrophages, with concomitant IL‐1β and chemokine release, leading to neutrophil infiltration. FasL signaling plays a critical role in models of acute lung injury, idiopathic pulmonary fibrosis and silicosis; blockade of Fas‐FasL interactions either prevents or attenuates pulmonary inflammation and fibrosis. Serologic and immunohistochemical studies in patients support a major pathogenic role of Fas and FasL molecules in inflammatory lung diseases. Identification of the pathogenic role of FasL could facilitate the discovery of more effective treatments for currently untreatable inflammatory lung diseases.

Keywords: Fas ligand, apoptosis, inflammation, neutrophil, macrophage, phagocytosis, fibrosis, lung, injury, silicosis

References

  • 1. Sheppard D., Pulmonary fibrosis: a cellular overreaction or a failure of communication?, J. Clin. Invest., 107: 1501–1502, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2. Rudin C.M., Thompson C.B., Apoptosis and disease: regulation and clinical relevance of programmed cell death, Annu. Rev. Med., 48: 267–281, 1997. [DOI] [PubMed] [Google Scholar]
  • 3. Nagata S., Fas ligand‐induced apoptosis, Annu. Rev. Genet., 33: 29–55, 1999. [DOI] [PubMed] [Google Scholar]
  • 4. 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., 19: 537–542, 1998. [DOI] [PubMed] [Google Scholar]
  • 5. DosReis G.A., Borges V.M., Role of Fas ligand‐induced apoptosis in pulmonary inflammation and injury, Curr. Drug Targets Inflamm. Allergy, 2: 161–167, 2003. [DOI] [PubMed] [Google Scholar]
  • 6. 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, 270: 1189–1192, 1995. [DOI] [PubMed] [Google Scholar]
  • 7. Kavurma M.M., Khachigian L.M., Signaling and transcriptional control of Fas ligand gene expression, Cell Death Differ., 10: 36–44, 2003. [DOI] [PubMed] [Google Scholar]
  • 8. Sharma K., Wang R.X., Zhang L.Y., Yin D.L., Luo X.Y., Solomon J.C., Jiang R.F., Markos K., Davidson W., Scott D.W., Shi Y.F., Death the Fas way: regulation and pathophysiology of CD95 and its ligand, Pharmacol. Ther., 88: 333–347, 2000. [DOI] [PubMed] [Google Scholar]
  • 9. Shangary S., Lerner E.C., Zhan Q., Corey S.J., Smithgall T.E., Baskaran R., Lyn regulates the cell death response to ultraviolet radiation through c‐Jun N terminal kinase‐dependent Fas ligand activation, Exp. Cell Res., 289: 67–76, 2003. [DOI] [PubMed] [Google Scholar]
  • 10. Bauer M.K., Vogt M., Los M., Siegel J., Wesselborg S., Schulze‐Osthoff K., Role of reactive oxygen intermediates in activation‐induced CD95 (APO‐1/Fas) ligand expression, J. Biol. Chem., 273: 8048–8055, 1998. [DOI] [PubMed] [Google Scholar]
  • 11. Fubini B., Hubbard A., Reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation by silica in inflammation and fibrosis, Free Radic. Biol. Med., 34: 1507–1516, 2003. [DOI] [PubMed] [Google Scholar]
  • 12. Apenberg S., Freyberg M.A., Friedl P., Shear stress induces apoptosis in vascular smooth muscle cells via an autocrine Fas/FasL pathway, Biochem. Biophys. Res. Commun., 310: 355–359, 2003. [DOI] [PubMed] [Google Scholar]
  • 13. Thome M., Tschopp J., Regulation of lymphocyte proliferation and death by FLIP, Nat. Rev. Immunol., 1: 50–58, 2001. [DOI] [PubMed] [Google Scholar]
  • 14. Seino K., Kayagaki N., Okumura K., Yagita H., Antitumor effect of locally produced CD95 ligand, Nat. Med., 3: 165–170, 1997. [DOI] [PubMed] [Google Scholar]
  • 15. Hohlbaum A.M., Gregory M.S., Ju S.T., Marshak Rothstein, A. , Fas ligand engagement of resident peritoneal macrophages in vivo induces apoptosis and the production of neutrophil chemotactic factors, J. Immunol., 167: 6217–6224, 2001. [DOI] [PubMed] [Google Scholar]
  • 16. Kataoka T., Budd R.C., Holler N., Thome M., Martinon F., Irmler M., Burns K., Hahne M., Kennedy N., Kovacsovics M., Tschopp J., The caspase‐8 FLIP promotes activation of NF‐kB and Erk signaling pathways, Curr. Biol., 10: 640–648, 2000. [DOI] [PubMed] [Google Scholar]
  • 17. Hagimoto N., Kuwano K., Kawasaki M., Yoshimi M., Kanako Y., Kunitake R., Maeyama T., Tanaka T., Hara N., Induction of IL‐8 secretion and apoptosis in bronchiolar epithelial cells by Fas ligation, Am. J. Respir. Cell Mol. Biol., 21: 436–445, 1999. [DOI] [PubMed] [Google Scholar]
  • 18. Park D.R., Thomsen A.R., Frevert C.W., Pham U., Skerrett S.J., Kiener P.A., Liles W.C., Fas (CD95) induces proinflammatory cytokine responses by human monocytes and monocyte‐derived macrophages, J. Immunol., 170: 6209–6216, 2003. [DOI] [PubMed] [Google Scholar]
  • 19. Faouzi S., Burckhardt B.E., Hanson J.C., Campe C.B., Schrum L.W., Rippe R.A., Maher J.J., Anti‐Fas induces hepatic chemokines and promotes inflammation by an NFkB independent, caspase‐3‐dependent pathway, J. Biol. Chem., 276: 49077–49082, 2001. [DOI] [PubMed] [Google Scholar]
  • 20. Ahn J.H., Park S.M., Cho H.S., Lee M.S., Yoon J.B., Vilcek J., Lee T.H., Non‐apoptotic signaling pathways activated by soluble Fas ligand in serum‐starved human fibroblasts; mitogen‐activated protein kinases and NF‐kB dependent gene expression, J. Biol. Chem., 276: 47100–47106, 2001. [DOI] [PubMed] [Google Scholar]
  • 21. Schaub F.J., Han D.K., Liles W.C., Adams L.D., Coats S.A., Ramachandran R.K., Seifert R.A., Schwartz S.M., Bowen‐Pope DF., Fas/FADD‐mediated activation of a specific program of inflammatory gene expression in vascular smooth muscle cells, Nat. Med., 6: 790–796, 2000. [DOI] [PubMed] [Google Scholar]
  • 22. Balibrea J.L., Arias‐Diaz J., Acute respiratory distress syndrome in the septic surgical patient, World J. Surg., 27: 1274–1284, 2003. [DOI] [PubMed] [Google Scholar]
  • 23. Hagimoto N., Kuwano K., Miyazaki H., Kunitake R., Fujita M., Kawasaki M., Kaneko Y., Hara N., Induction of apoptosis and pulmonary fibrosis in mice in response to ligation of Fas antigen, Am. J. Respir. Cell Mol. Biol., 17: 272–278, 1997. [DOI] [PubMed] [Google Scholar]
  • 24. Matute‐Bello G., Winn R.K., Jonas M., Chi E.Y., Martin T.R., Liles W.C., Fas (CD95) induces alveolar epithelial cell apoptosis in vivo: implications for acute pulmonary inflammation, Am. J. Pathol., 158: 153–161, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25. Faffe D.S., Seidl V.R., Chagas P.S.C., Gonalves‐de‐Moraes V.L., Capelozzi V.L., Rocco P.R.M., Zin W.A., Respiratory effects of lipopolysaccharide‐induced inflammatory lung injury in mice, Eur. Respir. J., 15: 85–91, 2000. [DOI] [PubMed] [Google Scholar]
  • 26. Kitamura Y., Hashimoto S., Mizuta N., Kobayashi A., Kooguchi K., Fujiwara I., Nakajima H., Fas/FasL dependent apoptosis of alveolar cells after lipopolysaccharide‐induced lung injury in mice, Am. J. Respir. Crit. Care Med., 163: 762–769, 2001. [DOI] [PubMed] [Google Scholar]
  • 27. Matute‐Bello G., Winn R.K., Martin T.R., Liles W.C., Sustained lipopolysaccharide‐induced lung inflammation in mice is attenuated by functional deficiency of the Fas/Fas ligand system, Clin. Diagn. Lab. Immunol., 11: 358–361, 2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28. Albertine K.H., Soulier M.F., Wang Z., Ishizaka A., Hashimoto S., Zimmerman G.A., Matthay M.A., Ware L.B., Fas and Fas ligand are up‐regulated in pulmonary edema fluid and lung tissue of patients with acute lung injury and the acute respiratory distress syndrome, Am. J. Pathol., 161: 1783–1796, 2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. Kuwano K., Miyazaki H., Hagimoto N., Kawasaki M., Fujita M., Kunitake R., Kaneko Y., Hara N., The involvement of Fas‐Fas ligand pathway in fibrosing lung diseases, Am. J. Respir. Cell Mol. Biol., 20: 53–60, 1999. [DOI] [PubMed] [Google Scholar]
  • 30. Kuwano K., Hagimoto N., Kawasaki M., Yatomi T., Nakamura N., Nagata S., Suda T., Kunitake R., Maeyama T., Miyazaki H., Hara N., Essential roles of the Fas‐Fas ligand pathway in the development of pulmonary fibrosis, J. Clin. Invest., 104: 13–19, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. Kuwano K., Kunitake R., Maeyama T., Hagimoto N., Kawasaki M., Matsuba T., Yoshimi M., Inoshima I., Yoshida K., Hara N., Attenuation of bleomycin‐induced pneumopathy in mice by a caspase inhibitor, Am. J. Physiol. Lung Cell. Mol. Physiol., 280: L316‐L325, 2001. [DOI] [PubMed] [Google Scholar]
  • 32. Hao Z., Hampel B., Yagita H., Rajewsky K., T‐cell specific ablation of Fas leads to Fas ligand‐mediated lymphocyte depletion and inflammatory pulmonary fibrosis, J. Exp. Med., 199: 1355–1365, 2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33. Mossman B.T., Churg A., Mechanisms in the pathogenesis of asbestosis and silicosis, Am. J. Respir. Crit. Care Med., 157: 1666–1680, 1998. [DOI] [PubMed] [Google Scholar]
  • 34. Iyer R., Holian A., Involvement of the ICE family of proteases in silica‐induced apoptosis in human alveolar macrophages, Am. J. Physiol., 273: L760‐L767, 1997. [DOI] [PubMed] [Google Scholar]
  • 35. Borges V.M., Falco H., Leite‐Junior J.H., Alvim L., Teixeira G.P., Russo M., Nébrega A.F., Lopes M.F., Rocco P.M., Davidson W.F., Linden R., Yagita H., Zin W.A., DosReis G.A., Fas ligand triggers pulmonary silicosis, J. Exp. Med., 194: 155–164, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36. Borges V.M., Lopes M.F., Falcao H., Leite‐Junior J.H., Rocco P.R., Davidson W.F., Linden R., Zin W.A., DosReis GA., Apoptosis underlies immunopathogenic mechanisms in acute silicosis, Am. J. Respir. Cell Mol. Biol., 27: 78–84, 2002. [DOI] [PubMed] [Google Scholar]
  • 37. Buonocore S., Paulart F., LeMoine A, Braun M, Salmon I, Van Meirvenne S., Thielemans K., Goldman M., Flamand V., Dendritic cells overexpressing CD95 (Fas) ligand elicit vigorous allospecific T‐cell responses in vivo, Blood, 101: 1469–1476, 2003. [DOI] [PubMed] [Google Scholar]
  • 38. Srivastava K.D., Rom W.N., Jagirdar J., Yie T.A., Gordon T., Tchou‐Wong K.M., Crucial role of interleukin‐ 1β and nitric oxide synthase in silica‐induced inflammation and apoptosis in mice, Am. J. Respir. Crit. Care Med., 165: 527–533, 2002. [DOI] [PubMed] [Google Scholar]
  • 39. Steenland K., Goldsmith D.F., Silica exposure and autoimmune diseases, Am. J. Ind. Med., 28: 603–608, 1995. [DOI] [PubMed] [Google Scholar]
  • 40. Cowie R.L., The epidemiology of tuberculosis in gold miners with silicosis., Am. J. Respir. Crit. Care Med., 150: 1460–1462, 1994. [DOI] [PubMed] [Google Scholar]
  • 41. Plotz P.H., The autoantibody repertoire: searching for order., Nat. Rev. Immunol., 3: 73–78, 2003. [DOI] [PubMed] [Google Scholar]
  • 42. Freire‐de‐Lima C.G., Nascimento D.O., Soares M.B., Bozza P.T., Castro‐Faria‐Neto H.C., DeMello F.G., DosReis G.A., Lopes M.F., Uptake of apoptotic cells drives the growth of a pathogenic trypanosome in macrophages, Nature, 403: 199–203, 2000. [DOI] [PubMed] [Google Scholar]
  • 43. Kolb M., Margetts P.J., Anthony D.C., Pitossi F., Gauldie J., Transient expression of IL‐1β induces acute lung injury and chronic repair leading to pulmonary fibrosis, J. Clin. Invest., 107: 1529–1536, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44. Sheppard D., Uses of expression microarrays in studies of pulmonary fibrosis, asthma, acute lung injury, and emphysema, Chest, 121: 21S‐25S, 2002. [DOI] [PubMed] [Google Scholar]
  • 45. Savill J., Dransfield I., Gregory C., Haslett C., A blast from the past: clearance of apoptotic cells regulates immune responses, Nat. Rev. Immunol., 2: 965–975, 2002. [DOI] [PubMed] [Google Scholar]
  • 46. Hu B., Sonstein J., Christensen P.J., Punturieri A., Curtis J.L., Deficient in vitro and in vivo phagocytosis of apoptotic T cells by resident murine alveolar macrophages, J. Immunol., 165: 2124–2133, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47. Medan D., Wang L., Yang X., Dokka S., Castranova V., Rojanasakul Y., Induction of neutrophil apoptosis and secondary necrosis during endotoxin‐induced pulmonary inflammation in mice, J. Cell. Physiol., 191: 320–326, 2002. [DOI] [PubMed] [Google Scholar]
  • 48. Ribeiro‐Gomes F.L., Otero A.C., Gomes N.A., Moniz‐de‐Souza M.C.A., Cysne‐Finkelstein L., Calich V.L., Arnholdt A.C., Coutinho S.G., Lopes M.F., DosReis G.A., Macrophage interactions with neutrophils regulate Leishmania major infection, J. Immunol., 172: 4454–4462, 2004. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Cellular and Molecular Medicine are provided here courtesy of Blackwell Publishing

RESOURCES