Skip to main content
PMC home page
Thorax logoLink to Thorax
. 2000 Oct;55(10):842–847. doi: 10.1136/thorax.55.10.842

Reduced production of interleukin 12 by interferon γ primed alveolar macrophages from atopic asthmatic subjects

M Plummeridge 1, L Armstrong 1, M Birchall 1, A Millar 1
PMCID: PMC1745617  PMID: 10992536

Abstract

BACKGROUND—Asthma is characterised pathologically by an inflammatory pulmonary infiltrate rich in T helper (Th) 2 cells and eosinophils. Interleukin (IL)-12 is a heterodimeric cytokine critical for driving the development of uncommitted Th cells to express a Th 1 phenotype. Reduced pulmonary production of IL-12 may therefore play a role in the pathogenesis of asthma by contributing to the pulmonary cytokine imbalance seen in asthma.
METHODS—IL-12 p70 protein levels in bronchoalveolar lavage fluid and p70 protein levels and IL-12 messenger RNA in alveolar macrophage cultures from normal and atopic asthmatic subjects were measured.
RESULTS—There was a significant difference between the mean IL-12 p70 protein level in the bronchoalveolar lavage fluid from asthmatic subjects (37.5 pg/ml) and from normal subjects (131 pg/ml, p =0.04). Alveolar macrophages from asthmatic subjects produced significantly less IL-12 protein (30 pg/ml) and messenger RNA than those from normal subjects (69.5 pg/ml, p<0.005). These differences were not caused by inhibition of IL-12 production by IL-10 nor to generalised hyporesponsiveness of asthmatic alveolar macrophages from subjects to the effects of interferon (IFN)-γ.
CONCLUSIONS—Pulmonary IL-12 production is lower in asthmatic subjects. This reduction is not the result of generalised hyporesponsiveness to IFN-γ. Reduced IL-12 levels may contribute to the development of asthmatic pulmonary inflammation through dysregulation of Th cell development.



Full Text

The Full Text of this article is available as a PDF (171.6 KB).

Selected References

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

  1. Bach E. A., Aguet M., Schreiber R. D. The IFN gamma receptor: a paradigm for cytokine receptor signaling. Annu Rev Immunol. 1997;15:563–591. doi: 10.1146/annurev.immunol.15.1.563. [DOI] [PubMed] [Google Scholar]
  2. Borish L., Aarons A., Rumbyrt J., Cvietusa P., Negri J., Wenzel S. Interleukin-10 regulation in normal subjects and patients with asthma. J Allergy Clin Immunol. 1996 Jun;97(6):1288–1296. doi: 10.1016/s0091-6749(96)70197-5. [DOI] [PubMed] [Google Scholar]
  3. Galve-de Rochemonteix B., Nicod L. P., Dayer J. M. Tumor necrosis factor soluble receptor 75: the principal receptor form released by human alveolar macrophages and monocytes in the presence of interferon gamma. Am J Respir Cell Mol Biol. 1996 Mar;14(3):279–287. doi: 10.1165/ajrcmb.14.3.8845179. [DOI] [PubMed] [Google Scholar]
  4. Gavett S. H., Chen X., Finkelman F., Wills-Karp M. Depletion of murine CD4+ T lymphocytes prevents antigen-induced airway hyperreactivity and pulmonary eosinophilia. Am J Respir Cell Mol Biol. 1994 Jun;10(6):587–593. doi: 10.1165/ajrcmb.10.6.8003337. [DOI] [PubMed] [Google Scholar]
  5. Gavett S. H., O'Hearn D. J., Li X., Huang S. K., Finkelman F. D., Wills-Karp M. Interleukin 12 inhibits antigen-induced airway hyperresponsiveness, inflammation, and Th2 cytokine expression in mice. J Exp Med. 1995 Nov 1;182(5):1527–1536. doi: 10.1084/jem.182.5.1527. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Grewe M., Czech W., Morita A., Werfel T., Klammer M., Kapp A., Ruzicka T., Schöpf E., Krutmann J. Human eosinophils produce biologically active IL-12: implications for control of T cell responses. J Immunol. 1998 Jul 1;161(1):415–420. [PubMed] [Google Scholar]
  7. Harrison T. S., Levitz S. M. Role of IL-12 in peripheral blood mononuclear cell responses to fungi in persons with and without HIV infection. J Immunol. 1996 Jun 1;156(11):4492–4497. [PubMed] [Google Scholar]
  8. Hayes M. P., Wang J., Norcross M. A. Regulation of interleukin-12 expression in human monocytes: selective priming by interferon-gamma of lipopolysaccharide-inducible p35 and p40 genes. Blood. 1995 Jul 15;86(2):646–650. [PubMed] [Google Scholar]
  9. Humbert M., Durham S. R., Ying S., Kimmitt P., Barkans J., Assoufi B., Pfister R., Menz G., Robinson D. S., Kay A. B. IL-4 and IL-5 mRNA and protein in bronchial biopsies from patients with atopic and nonatopic asthma: evidence against "intrinsic" asthma being a distinct immunopathologic entity. Am J Respir Crit Care Med. 1996 Nov;154(5):1497–1504. doi: 10.1164/ajrccm.154.5.8912771. [DOI] [PubMed] [Google Scholar]
  10. Isler P., de Rochemonteix B. G., Songeon F., Boehringer N., Nicod L. P. Interleukin-12 production by human alveolar macrophages is controlled by the autocrine production of interleukin-10. Am J Respir Cell Mol Biol. 1999 Feb;20(2):270–278. doi: 10.1165/ajrcmb.20.2.3313. [DOI] [PubMed] [Google Scholar]
  11. John M., Lim S., Seybold J., Jose P., Robichaud A., O'Connor B., Barnes P. J., Chung K. F. Inhaled corticosteroids increase interleukin-10 but reduce macrophage inflammatory protein-1alpha, granulocyte-macrophage colony-stimulating factor, and interferon-gamma release from alveolar macrophages in asthma. Am J Respir Crit Care Med. 1998 Jan;157(1):256–262. doi: 10.1164/ajrccm.157.1.9703079. [DOI] [PubMed] [Google Scholar]
  12. Kips J. C., Brusselle G. J., Joos G. F., Peleman R. A., Tavernier J. H., Devos R. R., Pauwels R. A. Interleukin-12 inhibits antigen-induced airway hyperresponsiveness in mice. Am J Respir Crit Care Med. 1996 Feb;153(2):535–539. doi: 10.1164/ajrccm.153.2.8564093. [DOI] [PubMed] [Google Scholar]
  13. Kobayashi M., Fitz L., Ryan M., Hewick R. M., Clark S. C., Chan S., Loudon R., Sherman F., Perussia B., Trinchieri G. Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J Exp Med. 1989 Sep 1;170(3):827–845. doi: 10.1084/jem.170.3.827. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kraft M., Djukanovic R., Wilson S., Holgate S. T., Martin R. J. Alveolar tissue inflammation in asthma. Am J Respir Crit Care Med. 1996 Nov;154(5):1505–1510. doi: 10.1164/ajrccm.154.5.8912772. [DOI] [PubMed] [Google Scholar]
  15. Kraft M., Martin R. J., Wilson S., Djukanovic R., Holgate S. T. Lymphocyte and eosinophil influx into alveolar tissue in nocturnal asthma. Am J Respir Crit Care Med. 1999 Jan;159(1):228–234. doi: 10.1164/ajrccm.159.1.9804033. [DOI] [PubMed] [Google Scholar]
  16. Lensmar C., Prieto J., Dahlén B., Eklund A., Grunewald J., Roquet A. Airway inflammation and altered alveolar macrophage phenotype pattern after repeated low-dose allergen exposure of atopic asthmatic subjects. Clin Exp Allergy. 1999 Dec;29(12):1632–1640. doi: 10.1046/j.1365-2222.1999.00757.x. [DOI] [PubMed] [Google Scholar]
  17. Magnan A., van Pee D., Bongrand P., Vervloet D. Alveolar macrophage interleukin (IL)-10 and IL-12 production in atopic asthma. Allergy. 1998 Nov;53(11):1092–1095. doi: 10.1111/j.1398-9995.1998.tb03821.x. [DOI] [PubMed] [Google Scholar]
  18. Manetti R., Parronchi P., Giudizi M. G., Piccinni M. P., Maggi E., Trinchieri G., Romagnani S. Natural killer cell stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells. J Exp Med. 1993 Apr 1;177(4):1199–1204. doi: 10.1084/jem.177.4.1199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Martin T. R. Cytokines and the acute respiratory distress syndrome (ARDS): a question of balance. Nat Med. 1997 Mar;3(3):272–273. doi: 10.1038/nm0397-272. [DOI] [PubMed] [Google Scholar]
  20. Maruo S., Toyo-oka K., Oh-hora M., Tai X. G., Iwata H., Takenaka H., Yamada S., Ono S., Hamaoka T., Kobayashi M. IL-12 produced by antigen-presenting cells induces IL-2-independent proliferation of T helper cell clones. J Immunol. 1996 Mar 1;156(5):1748–1755. [PubMed] [Google Scholar]
  21. Minshall E. M., Hogg J. C., Hamid Q. A. Cytokine mRNA expression in asthma is not restricted to the large airways. J Allergy Clin Immunol. 1998 Mar;101(3):386–390. doi: 10.1016/s0091-6749(98)70252-0. [DOI] [PubMed] [Google Scholar]
  22. Naseer T., Minshall E. M., Leung D. Y., Laberge S., Ernst P., Martin R. J., Hamid Q. Expression of IL-12 and IL-13 mRNA in asthma and their modulation in response to steroid therapy. Am J Respir Crit Care Med. 1997 Mar;155(3):845–851. doi: 10.1164/ajrccm.155.3.9117015. [DOI] [PubMed] [Google Scholar]
  23. Robinson D. S., Hamid Q., Ying S., Tsicopoulos A., Barkans J., Bentley A. M., Corrigan C., Durham S. R., Kay A. B. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med. 1992 Jan 30;326(5):298–304. doi: 10.1056/NEJM199201303260504. [DOI] [PubMed] [Google Scholar]
  24. Robinson D. S., Ying S., Bentley A. M., Meng Q., North J., Durham S. R., Kay A. B., Hamid Q. Relationships among numbers of bronchoalveolar lavage cells expressing messenger ribonucleic acid for cytokines, asthma symptoms, and airway methacholine responsiveness in atopic asthma. J Allergy Clin Immunol. 1993 Sep;92(3):397–403. doi: 10.1016/0091-6749(93)90118-y. [DOI] [PubMed] [Google Scholar]
  25. Spiteri M. A., Knight R. A., Jeremy J. Y., Barnes P. J., Chung K. F. Alveolar macrophage-induced suppression of peripheral blood mononuclear cell responsiveness is reversed by in vitro allergen exposure in bronchial asthma. Eur Respir J. 1994 Aug;7(8):1431–1438. doi: 10.1183/09031936.94.07081431. [DOI] [PubMed] [Google Scholar]
  26. Tang C., Rolland J. M., Li X., Ward C., Bish R., Walters E. H. Alveolar macrophages from atopic asthmatics, but not atopic nonasthmatics, enhance interleukin-5 production by CD4+ T cells. Am J Respir Crit Care Med. 1998 Apr;157(4 Pt 1):1120–1126. doi: 10.1164/ajrccm.157.4.9706118. [DOI] [PubMed] [Google Scholar]
  27. Tormey V. J., Leonard C., Faul J., Bernard S., Burke C. M., Poulter L. W. Dysregulation of monocyte differentiation in asthmatic subjects is reversed by IL-10. Clin Exp Allergy. 1998 Aug;28(8):992–998. doi: 10.1046/j.1365-2222.1998.00359.x. [DOI] [PubMed] [Google Scholar]
  28. Trinchieri G. Immunobiology of interleukin-12. Immunol Res. 1998;17(1-2):269–278. doi: 10.1007/BF02786451. [DOI] [PubMed] [Google Scholar]
  29. Viksman M. Y., Liu M. C., Bickel C. A., Schleimer R. P., Bochner B. S. Phenotypic analysis of alveolar macrophages and monocytes in allergic airway inflammation. I. Evidence for activation of alveolar macrophages, but not peripheral blood monocytes, in subjects with allergic rhinitis and asthma. Am J Respir Crit Care Med. 1997 Mar;155(3):858–863. doi: 10.1164/ajrccm.155.3.9117017. [DOI] [PubMed] [Google Scholar]
  30. van der Pouw Kraan T. C., Boeije L. C., de Groot E. R., Stapel S. O., Snijders A., Kapsenberg M. L., van der Zee J. S., Aarden L. A. Reduced production of IL-12 and IL-12-dependent IFN-gamma release in patients with allergic asthma. J Immunol. 1997 Jun 1;158(11):5560–5565. [PubMed] [Google Scholar]

Articles from Thorax are provided here courtesy of BMJ Publishing Group

RESOURCES