Skip to main content
SpringerLink
Log in

Antigen-induced alveolitis: Cytokine production in a mouse model

  • Original Articles
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Mice of the C57BL/6 strain were injected intraperitoneally with 108 sheep red blood cells (SRBC), then instilled intratracheally with 108 SRBC two to three weeks later. After a single intratracheal exposure, a significant cellular infiltrate occurred, composed mostly of macrophages and lymphocytes. Lymphocytes proliferated significantly in response to SRBC antigen in vitro and released interleukin-2 (IL-2). Alveolar macrophages isolated from mice challenged with SRBC released higher levels of IL-1, IL-6, and tumor necrosis factor-alpha (TNF-α) upon in vitro lipopolysaccharide (LPS) stimulation compared to unprimed, challenged mice or mice receiving intraperitoneal SRBC alone. Lymphocytes from primed mice challenged three times with SRBC proliferated significantly less in response to the antigen than mice receiving one SRBC challenge and released significant levels of interferon gamma (IFN-γ). Bronchoalveolar macrophages isolated from primed mice given three SRBC challenges released slightly higher levels of TNF-α and IL-6 in response to LPS than those from unprimed mice. After the third instillation, levels of hydroxyproline in the lungs increased significantly, indicative of a fibrotic reaction. Neutralization of IL-1 (by anti-mouse type 1 IL-1 receptor) or TNF-α resulted in the partial abrogation of the initial neutrophil influx, with some effect on the subsequent lymphocyte and macrophage influx. Blocking IL-1 or IL-2 but not TNF-α also resulted in a significant decrease in lung hydroxyproline increase, as well as lung granulomatous response and fibrosis. Overall, these results suggest that lymphoproliferation in the lungs in response to an antigen can result in fibrosis, mediated in part by IL-2 and IL-1.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. McLeod, E., J. L. Caldwell, andH. B. Kaltreider. 1978. Pulmonary immune responses of inbred mice. Appearance of antibody-forming cells in C57BL/6 mice after intrapulmonary or systemic immunization with sheep erythrocytes.Am. Rev. Respir. Dis. 118:561.

    PubMed  Google Scholar 

  2. Kaltreider, H. B., J. L. Curtis, andS. M. Arraj. 1987. The mechanism of appearance of specific antibody-forming cells in lungs of inbred mice after immunization with sheep erythrocytes intratracheally.Am. Rev. Respir. Dis. 135:87.

    PubMed  Google Scholar 

  3. Curtis, J. L., M. L. Warnock, S. M. Arraj, andH. B. Kaltreider. 1990. Histologic analysis of an immune response in the lung parenchyma of mice.Am. J. Pathol. 137:689.

    PubMed  Google Scholar 

  4. Kelley, J. 1990. Cytokines of the lung.Am. Rev. Respir. Dis 141:765.

    PubMed  Google Scholar 

  5. Rich, E. A., D. J. Tweardy, H. Fujiwara, andJ. J. Ellner. 1987. Spectrum of immuno-regulatory functions and properties of human alveolar macrophages.Am. Rev. Respir. Dis. 136:258.

    PubMed  Google Scholar 

  6. Garcia, H., L. Salter-Cid, andJ. Stein-Strelein. 1992. Persistent interleukin-2 activity and molecular evidence for expression of lymphotoxin in the hapten-immune model for pulmonary interstitial fibrosis.Am. J. Respir. Cell Mol. Biol. 6:22.

    PubMed  Google Scholar 

  7. Denis, M., andM. Laviolette. 1992. Murine hypersensitivity pneumonitis; a study of cellular infiltrates and cytokine production and its modulation by cyclosporin A.Am. J. Respir. Cell Mol. Biol. 6:68.

    PubMed  Google Scholar 

  8. Elias, J. A., B. Freundlich, J. A. Kern, andJ. Rosenbloom. 1990. Cytokine networks in the regulation of inflammation and fibrosis in the lung.Chest 97:1439.

    PubMed  Google Scholar 

  9. Ryan, L. K., andM. H. Karol. 1991. Release of tumor necrosis factor in guinea pigs upon acute inhalation of cotton dust.Am. J. Respir. Cell Mol. Biol. 5:93.

    PubMed  Google Scholar 

  10. Everson, M. P., andD. B. Chandler. 1992. Changes in distribution, morphology, and tumor necrosis factor-α secretion of alveolar macrophage subpopulations during the development of bleomycin-induced pulmonary fibrosis.Am. J. Pathol. 140:503.

    PubMed  Google Scholar 

  11. Piguet, P. F., M. A. Collart, G. E. Grau, Y. Kapanci, andP. Vassalli. 1989. Tumor necrosis factor/cachectin plays a key role in bleomycin-induced pneumopathy and fibrosis.J. Exp. Med. 170:655.

    PubMed  Google Scholar 

  12. Denis, M., M. Fournier, J. Tardif, andM. Laviolette. 1991. Tumor necrosis factor plays an essential role in determining hypersensitivity pneumonitis in a mouse model.Am. J. Respir. Cell Mol. Biol. 5:477.

    PubMed  Google Scholar 

  13. McIntyre, K. W., G. J. Stepan, K. D. Kolinsky, W. R. Benjamin, J. M. Plocinski, K. L. Kaffka, C. A. Campen, R. A. Chizzonite, andP. L. Kilian. 1991. Inhibition of IL-1 binding and bioactivity in vitro and modulation of acute inflammation in vivo by IL-1 receptor antagonist and anti-IL-1 receptor monoclonal antibody.J. Exp. Med. 173:931.

    PubMed  Google Scholar 

  14. Hogan, M. M., andS. N. Vogel. 1988. Production of TNF by rIFN-γ-primed C3H/HeJ (Lpsd) macrophages requires the presence of lipid-A-associated proteins.J. Immunol. 141:4196.

    PubMed  Google Scholar 

  15. Kurt-Jones, E. A., D. I. Beller, S. B. Mizel, andE. R. Unanue. 1985. Identification of a membrane-associated interleukin-1 in macrophages.Proc. Natl. Acad. Sci. U.S.A. 82:1204.

    PubMed  Google Scholar 

  16. Brakenhoff, J. P., E. R. DeGroot, R. F. Evers, H. Pannekoek, andL. A. Aarden. 1987. Molecular cloning and expression of hybridoma growth factor inE. coli.J. Immunol. 139:4116.

    PubMed  Google Scholar 

  17. Gearing, A. J., andC. R. Byrd. 1987. Production and assay of interleukin-2.In Lymphokines and Interferons; A Practical Approach. Edited by M. J. Clemens, A. G. Morris, and A. J. H. Gearing, editors. Oxford Press, London, 291–301.

    Google Scholar 

  18. Schreiber, R. D., L. J. Hicks, A. Celada, N. A. Buchmeier, andP. W. Gray. 1985. Monoclonal macrophage activation and antiviral activity.J. Immunol. 134:1609.

    PubMed  Google Scholar 

  19. Huszar, G. J., andJ. Maiocco. 1979. Monitoring of collagen and non-collagen fragments in chromatography of protein mixtures.Anal. Biochem. 105:424.

    Google Scholar 

  20. Kaltreider, H. B., J. L. Caldwell, andP. K. Byrd. 1986. The capacity of normal murine alveolar macrophages to function as antigen-presenting cells for the initiation of primary antibody-forming cells in response to sheep erythrocytes in vitro.Am. Rev. Respir. Dis. 133:1097.

    PubMed  Google Scholar 

  21. Curtis, J. L., P. K. Boyd, M. L. Warnock, andH. B. Kaltreider. 1991. Requirement of CD4-positive T cells for cellular recruitment to the lungs of mice in response to a particulate intratracheal antigen.J. Clin. Invest. 88:1244.

    PubMed  Google Scholar 

  22. Kaltreider, H. B., P. K. Boyd, andJ. L. Curtis. 1988. Expression of Ia by murine alveolar macrophages is up-regulated during the evolution of a specific immune response in pulmonary parenchyma.Am. Rev. Respir. Dis. 137:1411.

    PubMed  Google Scholar 

  23. Hunninghake, G. W., G. N. Bedell, D. C. Zavala, M. Monick, andM. Brady. 1983. Role of interleukin-2 release by lung T cells in active pulmonary sarcoidosis.Am. Rev. Respir. Dis. 128:634.

    PubMed  Google Scholar 

  24. McCombs, C. C., J. P. Michalski, B. T. Westerfield, andR. W. Light. 1982. Human alveolar macrophages suppress the proliferative response of peripheral blood lymphocytes.Chest 82:266.

    PubMed  Google Scholar 

  25. Ettensohn, D. B., P. A. Lalor, andN. J. Roberts. 1988. Human alveolar macrophage suppression of lymphocyte proliferation.Am. Rev. Respir. Dis. 137:765.

    PubMed  Google Scholar 

  26. Paine, R., C. H. Mody, A. Chavis, M. A. Spahr, L. A. Turka, andG. B. Toews. 1991. Alveolar epithelial cells block lymphocyte proliferation in vitro without inhibiting activation.Am. J. Respir. Cell Mol. Biol. 5:221.

    PubMed  Google Scholar 

  27. Holt, P. G. 1980. Alveolar macrophages.Cell Immunol. 50:210.

    PubMed  Google Scholar 

  28. Berman, J. S., D. J. Beer, A.C. Theodor, H. Kornfeld, J. Bernado, andD. M. Center. 1990. Lymphocyte recruitment to the lung.Am. Rev. Respir. Dis. 142:238.

    PubMed  Google Scholar 

  29. Sanders, M. E., Makgoba, M. W., andShaw, S. 1988. Human naïve and memory T cells; reinterpretation of helper-inducer and suppressor-inducer subsets.Immunol. Today 9:195.

    PubMed  Google Scholar 

  30. Dinarello, C. A. 1989. Interleukin-1 and its biologically related cytokines.Adv. Immunol. 44:153.

    PubMed  Google Scholar 

  31. Warren, J. S., K. R. Yabroff, D. G. Remick, S. L. Kunkel, S. W. Chensue, R. G. Kunkel, K. J. Johnson, andP. A. Ward 1989. Tumor necrosis factor participates in the pathogenesis of acute immune complex alveolitis in the rat.J. Clin. Invest. 84:1873.

    PubMed  Google Scholar 

  32. Strausz, J., D. N. Mannel, S. Pfeifer, A. Borkowski, R. Ferlinz, J. Muller-Quernheim. 1991. Spontaneous monokine release by alveolar macrophages in chronic sarcoidosis.Int. Arch. Allergy Appl. Immunol. 96:68.

    PubMed  Google Scholar 

  33. Baughman, R. P., S. A. Strohofer, J. Buschsbaum, andE. E. Lower. 1990. Release of tumor necrosis factor by alveolar macrophages of patients with sarcoidosis.J. Lab. Clin. Med. 115:36.

    PubMed  Google Scholar 

  34. Lecossier, D., D. Valeyre, A. Loiseau, J. P. Battesti, P. Sorler, andA. J. Hance. 1988. T lymphocytes recovered by bronchoalveolar lavage from normal subjects and patients with sarcoidosis are refractory to proliferative signals.Am. Rev. Respir. Dis. 137:592.

    PubMed  Google Scholar 

  35. Yamasaki, H., T.Kinoshita, T.Ohmura, M.Ando, K.Soda, T.Sakata, S.Araki, and K.Onoue. Lowered responsiveness of bronchoalveolar lavage T lymphocytes in hypersensitivity pneumonitis.Am. J. Respir. Cell Mol. Biol. 4:417.

  36. Hol, B. E., F. H. Krouwels, B. Bruinier, R. M. R. Reijneke, H. J. J. Mengelers, L. Koenderman, H. M. Jansen, andT. A. Out. 1992. Cloning of T lymphocytes from bronchoalveolar lavage fluid.Am. J. Respir. Cell Mol. Biol. 7:523.

    PubMed  Google Scholar 

  37. Smith, K. A. 1988. Interleukin-2; inception, impact and implications.Science 240:1169.

    PubMed  Google Scholar 

  38. Dinarello, C. A. 1991. The pro-inflammatory cytokines interleukin-1 and tumor necrosis factor and treatment of the septic shock syndrome.J. Infect. Dis. 163:1177.

    PubMed  Google Scholar 

  39. Elias, J. A., andJ. Zitnik. 1992. Cytokine-cytokine interactions in the context of cytokine networking.Am. J. Respir. Cell Mol. Biol. 7:365.

    PubMed  Google Scholar 

  40. Ulich, T. R., S. M. Yin, K. Z. Guo, J. Del Castillo, S. P. Eisenberg, andR. C. Thompson. 1991. The intratracheal administration of endotoxin and cytokines III. The interleukin-1 receptor antagonist (IL-1ra) inhibits endotoxin- and IL-1-induced acute inflammation.Am. J. Pathol. 138:521.

    PubMed  Google Scholar 

  41. Kline, J. N., D. A. Schwartz, M. M. Monick, C. S. Floerchinger, andG. W. Hunninghake. 1993. Relative release of interleukin-1β and interleukin-1 receptor antagonist by alveolar macrophages.Chest 104:47.

    PubMed  Google Scholar 

  42. Larsen, C. G., A. O. Anderson, E. Appella, J. J. Oppenheim, andK. Matsushima. 1989. The neutrophil-activating protein (NAP-1) is also chemotactic for T lymphocytes.Science 243:1464.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Pulmonary Research Unit, University of Sherbrooke, 3001, 12th Avenue N., J1H 5N4, Sherbrooke, Quebec, Canada

    Michel Denis & Denis Bisson

  2. Department of Anatomy and Cell Biology Faculty of Medecine, University of Sherbrooke, 3001, 12th Avenue N., J1H 5N4, Sherbrooke, Quebec, Canada

    Michel Denis

Authors
  1. Michel Denis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Denis Bisson
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Denis, M., Bisson, D. Antigen-induced alveolitis: Cytokine production in a mouse model. Inflammation 19, 157–177 (1995). https://doi.org/10.1007/BF01534459

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01534459

Keywords

Search

Navigation