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. 1995 Nov 1;182(5):1527–1536. doi: 10.1084/jem.182.5.1527

Interleukin 12 inhibits antigen-induced airway hyperresponsiveness, inflammation, and Th2 cytokine expression in mice

PMCID: PMC2192202  PMID: 7595222

Abstract

Allergic asthma is characterized by airway hyperresponsiveness and pulmonary eosinophilia, and may be mediated by T helper (Th) lymphocytes expressing a Th2 cytokine pattern. Interleukin (IL) 12 suppresses the expression of Th2 cytokines and their associated responses, including eosinophilia, serum immunoglobulin E, and mucosal mastocytosis. We have previously shown in a murine model that antigen- induced increases in airway hyperresponsiveness and pulmonary eosinophilia are CD4+ T cell dependent. We used this model to determine the ability of IL-12 to prevent antigen-induced increases in airway hyperresponsiveness, bronchoalveolar lavage (BAL) eosinophils, and lung Th2 cytokine expression. Sensitized A/J mice developed airway hyperresponsiveness and increased numbers of BAL eosinophils and other inflammatory cells after single or repeated intratracheal challenges with sheep red blood cell antigen. Pulmonary mRNA and protein levels of the Th2 cytokines IL-4 and IL-5 were increased after antigen challenge. Administration of IL-12 (1 microgram/d x 5 d) at the time of a single antigen challenge abolished the airway hyperresponsiveness and pulmonary eosinophilia and promoted an increase in interferon (IFN) gamma and decreases in IL-4 and IL-5 expression. The effects of IL-12 were partially dependent on IFN-gamma, because concurrent treatment with IL-12 and anti-IFN-gamma monoclonal antibody partially reversed the inhibition of airway hyperresponsiveness and eosinophilia by IL-12. Treatment of mice with IL-12 at the time of a second antigen challenge also prevented airway hyperresponsiveness and significantly reduced numbers of BAL inflammatory cells, reflecting the ability of IL-12 to inhibit responses associated with ongoing antigen-induced pulmonary inflammation. These data show that antigen-induced airway hyperresponsiveness and inflammation can be blocked by IL-12, which suppresses Th2 cytokine expression. Local administration of IL-12 may provide a novel immunotherapy for the treatment of pulmonary allergic disorders such as atopic asthma.

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Selected References

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  1. Afonso L. C., Scharton T. M., Vieira L. Q., Wysocka M., Trinchieri G., Scott P. The adjuvant effect of interleukin-12 in a vaccine against Leishmania major. Science. 1994 Jan 14;263(5144):235–237. doi: 10.1126/science.7904381. [DOI] [PubMed] [Google Scholar]
  2. Azzawi M., Bradley B., Jeffery P. K., Frew A. J., Wardlaw A. J., Knowles G., Assoufi B., Collins J. V., Durham S., Kay A. B. Identification of activated T lymphocytes and eosinophils in bronchial biopsies in stable atopic asthma. Am Rev Respir Dis. 1990 Dec;142(6 Pt 1):1407–1413. doi: 10.1164/ajrccm/142.6_Pt_1.1407. [DOI] [PubMed] [Google Scholar]
  3. Bentley A. M., Maestrelli P., Saetta M., Fabbri L. M., Robinson D. S., Bradley B. L., Jeffery P. K., Durham S. R., Kay A. B. Activated T-lymphocytes and eosinophils in the bronchial mucosa in isocyanate-induced asthma. J Allergy Clin Immunol. 1992 Apr;89(4):821–829. doi: 10.1016/0091-6749(92)90437-7. [DOI] [PubMed] [Google Scholar]
  4. Bentley A. M., Meng Q., Robinson D. S., Hamid Q., Kay A. B., Durham S. R. Increases in activated T lymphocytes, eosinophils, and cytokine mRNA expression for interleukin-5 and granulocyte/macrophage colony-stimulating factor in bronchial biopsies after allergen inhalation challenge in atopic asthmatics. Am J Respir Cell Mol Biol. 1993 Jan;8(1):35–42. doi: 10.1165/ajrcmb/8.1.35. [DOI] [PubMed] [Google Scholar]
  5. Bradley B. L., Azzawi M., Jacobson M., Assoufi B., Collins J. V., Irani A. M., Schwartz L. B., Durham S. R., Jeffery P. K., Kay A. B. Eosinophils, T-lymphocytes, mast cells, neutrophils, and macrophages in bronchial biopsy specimens from atopic subjects with asthma: comparison with biopsy specimens from atopic subjects without asthma and normal control subjects and relationship to bronchial hyperresponsiveness. J Allergy Clin Immunol. 1991 Oct;88(4):661–674. doi: 10.1016/0091-6749(91)90160-p. [DOI] [PubMed] [Google Scholar]
  6. Brunda M. J. Interleukin-12. J Leukoc Biol. 1994 Feb;55(2):280–288. doi: 10.1002/jlb.55.2.280. [DOI] [PubMed] [Google Scholar]
  7. Campbell H. D., Tucker W. Q., Hort Y., Martinson M. E., Mayo G., Clutterbuck E. J., Sanderson C. J., Young I. G. Molecular cloning, nucleotide sequence, and expression of the gene encoding human eosinophil differentiation factor (interleukin 5). Proc Natl Acad Sci U S A. 1987 Oct;84(19):6629–6633. doi: 10.1073/pnas.84.19.6629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Coffman R. L., Seymour B. W., Hudak S., Jackson J., Rennick D. Antibody to interleukin-5 inhibits helminth-induced eosinophilia in mice. Science. 1989 Jul 21;245(4915):308–310. doi: 10.1126/science.2787531. [DOI] [PubMed] [Google Scholar]
  9. Corrigan C. J., Kay A. B. CD4 T-lymphocyte activation in acute severe asthma. Relationship to disease severity and atopic status. Am Rev Respir Dis. 1990 Apr;141(4 Pt 1):970–977. doi: 10.1164/ajrccm/141.4_Pt_1.. [DOI] [PubMed] [Google Scholar]
  10. D'Andrea A., Rengaraju M., Valiante N. M., Chehimi J., Kubin M., Aste M., Chan S. H., Kobayashi M., Young D., Nickbarg E. Production of natural killer cell stimulatory factor (interleukin 12) by peripheral blood mononuclear cells. J Exp Med. 1992 Nov 1;176(5):1387–1398. doi: 10.1084/jem.176.5.1387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dalton D. K., Pitts-Meek S., Keshav S., Figari I. S., Bradley A., Stewart T. A. Multiple defects of immune cell function in mice with disrupted interferon-gamma genes. Science. 1993 Mar 19;259(5102):1739–1742. doi: 10.1126/science.8456300. [DOI] [PubMed] [Google Scholar]
  12. Del Prete G. F., De Carli M., D'Elios M. M., Maestrelli P., Ricci M., Fabbri L., Romagnani S. Allergen exposure induces the activation of allergen-specific Th2 cells in the airway mucosa of patients with allergic respiratory disorders. Eur J Immunol. 1993 Jul;23(7):1445–1449. doi: 10.1002/eji.1830230707. [DOI] [PubMed] [Google Scholar]
  13. Finkelman F. D., Katona I. M., Urban J. F., Jr, Holmes J., Ohara J., Tung A. S., Sample J. V., Paul W. E. IL-4 is required to generate and sustain in vivo IgE responses. J Immunol. 1988 Oct 1;141(7):2335–2341. [PubMed] [Google Scholar]
  14. Finkelman F. D., Madden K. B., Cheever A. W., Katona I. M., Morris S. C., Gately M. K., Hubbard B. R., Gause W. C., Urban J. F., Jr Effects of interleukin 12 on immune responses and host protection in mice infected with intestinal nematode parasites. J Exp Med. 1994 May 1;179(5):1563–1572. doi: 10.1084/jem.179.5.1563. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Galli S. J. New concepts about the mast cell. N Engl J Med. 1993 Jan 28;328(4):257–265. doi: 10.1056/NEJM199301283280408. [DOI] [PubMed] [Google Scholar]
  16. 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]
  17. Gerblich A. A., Salik H., Schuyler M. R. Dynamic T-cell changes in peripheral blood and bronchoalveolar lavage after antigen bronchoprovocation in asthmatics. Am Rev Respir Dis. 1991 Mar;143(3):533–537. doi: 10.1164/ajrccm/143.3.533. [DOI] [PubMed] [Google Scholar]
  18. Gleich G. J. The eosinophil and bronchial asthma: current understanding. J Allergy Clin Immunol. 1990 Feb;85(2):422–436. doi: 10.1016/0091-6749(90)90151-s. [DOI] [PubMed] [Google Scholar]
  19. Gundel R. H., Letts L. G., Gleich G. J. Human eosinophil major basic protein induces airway constriction and airway hyperresponsiveness in primates. J Clin Invest. 1991 Apr;87(4):1470–1473. doi: 10.1172/JCI115155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Heinzel F. P., Schoenhaut D. S., Rerko R. M., Rosser L. E., Gately M. K. Recombinant interleukin 12 cures mice infected with Leishmania major. J Exp Med. 1993 May 1;177(5):1505–1509. doi: 10.1084/jem.177.5.1505. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Iwamoto I., Nakajima H., Endo H., Yoshida S. Interferon gamma regulates antigen-induced eosinophil recruitment into the mouse airways by inhibiting the infiltration of CD4+ T cells. J Exp Med. 1993 Feb 1;177(2):573–576. doi: 10.1084/jem.177.2.573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kapsenberg M. L., Wierenga E. A., Bos J. D., Jansen H. M. Functional subsets of allergen-reactive human CD4+ T cells. Immunol Today. 1991 Nov;12(11):392–395. doi: 10.1016/0167-5699(91)90137-I. [DOI] [PubMed] [Google Scholar]
  23. Kiniwa M., Gately M., Gubler U., Chizzonite R., Fargeas C., Delespesse G. Recombinant interleukin-12 suppresses the synthesis of immunoglobulin E by interleukin-4 stimulated human lymphocytes. J Clin Invest. 1992 Jul;90(1):262–266. doi: 10.1172/JCI115846. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. 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]
  25. Lack G., Renz H., Saloga J., Bradley K. L., Loader J., Leung D. Y., Larsen G., Gelfand E. W. Nebulized but not parenteral IFN-gamma decreases IgE production and normalizes airways function in a murine model of allergen sensitization. J Immunol. 1994 Mar 1;152(5):2546–2554. [PubMed] [Google Scholar]
  26. Le Gros G., Ben-Sasson S. Z., Seder R., Finkelman F. D., Paul W. E. Generation of interleukin 4 (IL-4)-producing cells in vivo and in vitro: IL-2 and IL-4 are required for in vitro generation of IL-4-producing cells. J Exp Med. 1990 Sep 1;172(3):921–929. doi: 10.1084/jem.172.3.921. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lopez A. F., Sanderson C. J., Gamble J. R., Campbell H. D., Young I. G., Vadas M. A. Recombinant human interleukin 5 is a selective activator of human eosinophil function. J Exp Med. 1988 Jan 1;167(1):219–224. doi: 10.1084/jem.167.1.219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. MacGlashan D., Jr, White J. M., Huang S. K., Ono S. J., Schroeder J. T., Lichtenstein L. M. Secretion of IL-4 from human basophils. The relationship between IL-4 mRNA and protein in resting and stimulated basophils. J Immunol. 1994 Mar 15;152(6):3006–3016. [PubMed] [Google Scholar]
  29. Madden K. B., Urban J. F., Jr, Ziltener H. J., Schrader J. W., Finkelman F. D., Katona I. M. Antibodies to IL-3 and IL-4 suppress helminth-induced intestinal mastocytosis. J Immunol. 1991 Aug 15;147(4):1387–1391. [PubMed] [Google Scholar]
  30. 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]
  31. Morris S. C., Madden K. B., Adamovicz J. J., Gause W. C., Hubbard B. R., Gately M. K., Finkelman F. D. Effects of IL-12 on in vivo cytokine gene expression and Ig isotype selection. J Immunol. 1994 Feb 1;152(3):1047–1056. [PubMed] [Google Scholar]
  32. Moser R., Fehr J., Bruijnzeel P. L. IL-4 controls the selective endothelium-driven transmigration of eosinophils from allergic individuals. J Immunol. 1992 Aug 15;149(4):1432–1438. [PubMed] [Google Scholar]
  33. Mosmann T. R., Cherwinski H., Bond M. W., Giedlin M. A., Coffman R. L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986 Apr 1;136(7):2348–2357. [PubMed] [Google Scholar]
  34. Nakajima H., Iwamoto I., Tomoe S., Matsumura R., Tomioka H., Takatsu K., Yoshida S. CD4+ T-lymphocytes and interleukin-5 mediate antigen-induced eosinophil infiltration into the mouse trachea. Am Rev Respir Dis. 1992 Aug;146(2):374–377. doi: 10.1164/ajrccm/146.2.374. [DOI] [PubMed] [Google Scholar]
  35. Parronchi P., Macchia D., Piccinni M. P., Biswas P., Simonelli C., Maggi E., Ricci M., Ansari A. A., Romagnani S. Allergen- and bacterial antigen-specific T-cell clones established from atopic donors show a different profile of cytokine production. Proc Natl Acad Sci U S A. 1991 May 15;88(10):4538–4542. doi: 10.1073/pnas.88.10.4538. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. 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]
  37. 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]
  38. Robinson D., Hamid Q., Bentley A., Ying S., Kay A. B., Durham S. R. Activation of CD4+ T cells, increased TH2-type cytokine mRNA expression, and eosinophil recruitment in bronchoalveolar lavage after allergen inhalation challenge in patients with atopic asthma. J Allergy Clin Immunol. 1993 Aug;92(2):313–324. doi: 10.1016/0091-6749(93)90175-f. [DOI] [PubMed] [Google Scholar]
  39. Shaw R. J., Walsh G. M., Cromwell O., Moqbel R., Spry C. J., Kay A. B. Activated human eosinophils generate SRS-A leukotrienes following IgG-dependent stimulation. Nature. 1985 Jul 11;316(6024):150–152. doi: 10.1038/316150a0. [DOI] [PubMed] [Google Scholar]
  40. Stern A. S., Podlaski F. J., Hulmes J. D., Pan Y. C., Quinn P. M., Wolitzky A. G., Familletti P. C., Stremlo D. L., Truitt T., Chizzonite R. Purification to homogeneity and partial characterization of cytotoxic lymphocyte maturation factor from human B-lymphoblastoid cells. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6808–6812. doi: 10.1073/pnas.87.17.6808. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Svetić A., Finkelman F. D., Jian Y. C., Dieffenbach C. W., Scott D. E., McCarthy K. F., Steinberg A. D., Gause W. C. Cytokine gene expression after in vivo primary immunization with goat antibody to mouse IgD antibody. J Immunol. 1991 Oct 1;147(7):2391–2397. [PubMed] [Google Scholar]
  42. Walker C., Bode E., Boer L., Hansel T. T., Blaser K., Virchow J. C., Jr Allergic and nonallergic asthmatics have distinct patterns of T-cell activation and cytokine production in peripheral blood and bronchoalveolar lavage. Am Rev Respir Dis. 1992 Jul;146(1):109–115. doi: 10.1164/ajrccm/146.1.109. [DOI] [PubMed] [Google Scholar]
  43. Wardlaw A. J., Dunnette S., Gleich G. J., Collins J. V., Kay A. B. Eosinophils and mast cells in bronchoalveolar lavage in subjects with mild asthma. Relationship to bronchial hyperreactivity. Am Rev Respir Dis. 1988 Jan;137(1):62–69. doi: 10.1164/ajrccm/137.1.62. [DOI] [PubMed] [Google Scholar]
  44. White S. R., Ohno S., Munoz N. M., Gleich G. J., Abrahams C., Solway J., Leff A. R. Epithelium-dependent contraction of airway smooth muscle caused by eosinophil MBP. Am J Physiol. 1990 Oct;259(4 Pt 1):L294–L303. doi: 10.1152/ajplung.1990.259.4.L294. [DOI] [PubMed] [Google Scholar]
  45. Wynn T. A., Eltoum I., Cheever A. W., Lewis F. A., Gause W. C., Sher A. Analysis of cytokine mRNA expression during primary granuloma formation induced by eggs of Schistosoma mansoni. J Immunol. 1993 Aug 1;151(3):1430–1440. [PubMed] [Google Scholar]
  46. Wynn T. A., Eltoum I., Oswald I. P., Cheever A. W., Sher A. Endogenous interleukin 12 (IL-12) regulates granuloma formation induced by eggs of Schistosoma mansoni and exogenous IL-12 both inhibits and prophylactically immunizes against egg pathology. J Exp Med. 1994 May 1;179(5):1551–1561. doi: 10.1084/jem.179.5.1551. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Yamaguchi Y., Suda T., Ohta S., Tominaga K., Miura Y., Kasahara T. Analysis of the survival of mature human eosinophils: interleukin-5 prevents apoptosis in mature human eosinophils. Blood. 1991 Nov 15;78(10):2542–2547. [PubMed] [Google Scholar]

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