Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1998 Dec 15;102(12):2156–2164. doi: 10.1172/JCI2680

Corticosteroid-resistant bronchial asthma is associated with increased c-fos expression in monocytes and T lymphocytes.

S J Lane 1, I M Adcock 1, D Richards 1, C Hawrylowicz 1, P J Barnes 1, T H Lee 1
PMCID: PMC509170  PMID: 9854051

Abstract

Unstimulated peripheral blood mononuclear cells (PBMCs) from corticosteroid-resistant (CR) but not corticosteroid-sensitive (CS) asthmatics demonstrate increased activating peptide-1 (AP-1)- and decreased glucocorticoid receptor (GR)-DNA binding. We test whether these abnormalities are associated with excessive generation of c-fos, the inducible component of AP-1. The c-fos transcription rate, mRNA and protein levels, and GR-DNA binding were quantitated in PBMCs, T cells, and monocytes from CS, CR, and nonasthmatic subjects. There was a 1.7-, 4.2-, and 2.3-fold greater increase in the baseline c-fos transcription rate, mRNA expression, and protein levels, respectively, in PBMCs derived from CR compared with CS patients. At optimal stimulation with PMA, there was a 5.7-, 3.4-, and 2-fold greater increase in the c-fos transcription rate, mRNA accumulation, and protein levels, respectively, in CR compared with CS PBMCs. These abnormalities were detected in both the T cell and monocyte subpopulations. PMA stimulation converted PBMCs from a CS to a CR phenotype and was associated with direct interaction between c-Fos and the GR. Pretreatment of PBMCs from CR patients with c-fos antisense oligonucleotides enhanced GR-DNA binding activity in CR PBMCs stimulated with dexamethasone. We suggest that increased c-fos synthesis provides a major mechanism for the increased AP-1- and decreased GR- DNA binding seen in CR asthma.

Full Text

The Full Text of this article is available as a PDF (436.1 KB).

Selected References

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

  1. Adcock I. M., Lane S. J., Brown C. R., Lee T. H., Barnes P. J. Abnormal glucocorticoid receptor-activator protein 1 interaction in steroid-resistant asthma. J Exp Med. 1995 Dec 1;182(6):1951–1958. doi: 10.1084/jem.182.6.1951. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Adcock I. M., Lane S. J., Brown C. R., Peters M. J., Lee T. H., Barnes P. J. Differences in binding of glucocorticoid receptor to DNA in steroid-resistant asthma. J Immunol. 1995 Apr 1;154(7):3500–3505. [PubMed] [Google Scholar]
  3. Agertoft L., Pedersen S. Effects of long-term treatment with an inhaled corticosteroid on growth and pulmonary function in asthmatic children. Respir Med. 1994 May;88(5):373–381. doi: 10.1016/0954-6111(94)90044-2. [DOI] [PubMed] [Google Scholar]
  4. Angel P., Karin M. The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim Biophys Acta. 1991 Dec 10;1072(2-3):129–157. doi: 10.1016/0304-419x(91)90011-9. [DOI] [PubMed] [Google Scholar]
  5. Barnes P. J. Inhaled glucocorticoids for asthma. N Engl J Med. 1995 Mar 30;332(13):868–875. doi: 10.1056/NEJM199503303321307. [DOI] [PubMed] [Google Scholar]
  6. Corrigan C. J., Brown P. H., Barnes N. C., Szefler S. J., Tsai J. J., Frew A. J., Kay A. B. Glucocorticoid resistance in chronic asthma. Glucocorticoid pharmacokinetics, glucocorticoid receptor characteristics, and inhibition of peripheral blood T cell proliferation by glucocorticoids in vitro. Am Rev Respir Dis. 1991 Nov;144(5):1016–1025. doi: 10.1164/ajrccm/144.5.1016. [DOI] [PubMed] [Google Scholar]
  7. Djukanović R., Wilson J. W., Britten K. M., Wilson S. J., Walls A. F., Roche W. R., Howarth P. H., Holgate S. T. Effect of an inhaled corticosteroid on airway inflammation and symptoms in asthma. Am Rev Respir Dis. 1992 Mar;145(3):669–674. doi: 10.1164/ajrccm/145.3.669. [DOI] [PubMed] [Google Scholar]
  8. Gniadecki R. A vitamin D analogue KH 1060 activates the protein kinase C-c-fos signalling pathway to stimulate epidermal proliferation in murine skin. J Endocrinol. 1994 Dec;143(3):521–525. doi: 10.1677/joe.0.1430521. [DOI] [PubMed] [Google Scholar]
  9. Haahtela T., Järvinen M., Kava T., Kiviranta K., Koskinen S., Lehtonen K., Nikander K., Persson T., Selroos O., Sovijärvi A. Effects of reducing or discontinuing inhaled budesonide in patients with mild asthma. N Engl J Med. 1994 Sep 15;331(11):700–705. doi: 10.1056/NEJM199409153311103. [DOI] [PubMed] [Google Scholar]
  10. Hanazawa S., Takeshita A., Amano S., Semba T., Nirazuka T., Katoh H., Kitano S. Tumor necrosis factor-alpha induces expression of monocyte chemoattractant JE via fos and jun genes in clonal osteoblastic MC3T3-E1 cells. J Biol Chem. 1993 May 5;268(13):9526–9532. [PubMed] [Google Scholar]
  11. Kerppola T. K., Luk D., Curran T. Fos is a preferential target of glucocorticoid receptor inhibition of AP-1 activity in vitro. Mol Cell Biol. 1993 Jun;13(6):3782–3791. doi: 10.1128/mcb.13.6.3782. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kreisberg J. I., Radnik R. A., Ayo S. H., Garoni J., Saikumar P. High glucose elevates c-fos and c-jun transcripts and proteins in mesangial cell cultures. Kidney Int. 1994 Jul;46(1):105–112. doi: 10.1038/ki.1994.249. [DOI] [PubMed] [Google Scholar]
  13. Lane S. J., Arm J. P., Staynov D. Z., Lee T. H. Chemical mutational analysis of the human glucocorticoid receptor cDNA in glucocorticoid-resistant bronchial asthma. Am J Respir Cell Mol Biol. 1994 Jul;11(1):42–48. doi: 10.1165/ajrcmb.11.1.8018337. [DOI] [PubMed] [Google Scholar]
  14. Lane S. J., Lee T. H. Corticosteroid resistance in other disease states and tissues. Am J Respir Crit Care Med. 1996 Aug;154(2 Pt 2):S62–S65. doi: 10.1164/ajrccm/154.2_Pt_2.S62. [DOI] [PubMed] [Google Scholar]
  15. Lane S. J., Lee T. H. Glucocorticoid receptor characteristics in monocytes of patients with corticosteroid-resistant bronchial asthma. Am Rev Respir Dis. 1991 May;143(5 Pt 1):1020–1024. doi: 10.1164/ajrccm/143.5_Pt_1.1020. [DOI] [PubMed] [Google Scholar]
  16. Lane S. J., Lee T. H. Mechanisms of corticosteroid resistance in asthmatic patients. Int Arch Allergy Immunol. 1997 May-Jul;113(1-3):193–195. doi: 10.1159/000237544. [DOI] [PubMed] [Google Scholar]
  17. Lane S. J., Lee T. H. Mononuclear cells in corticosteroid-resistant asthma. Am J Respir Crit Care Med. 1996 Aug;154(2 Pt 2):S49–S52. doi: 10.1164/ajrccm/154.2_Pt_2.S49. [DOI] [PubMed] [Google Scholar]
  18. Leung D. Y., Martin R. J., Szefler S. J., Sher E. R., Ying S., Kay A. B., Hamid Q. Dysregulation of interleukin 4, interleukin 5, and interferon gamma gene expression in steroid-resistant asthma. J Exp Med. 1995 Jan 1;181(1):33–40. doi: 10.1084/jem.181.1.33. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Mori A., Kaminuma O., Suko M., Inoue S., Ohmura T., Hoshino A., Asakura Y., Miyazawa K., Yokota T., Okumura Y. Two distinct pathways of interleukin-5 synthesis in allergen-specific human T-cell clones are suppressed by glucocorticoids. Blood. 1997 Apr 15;89(8):2891–2900. [PubMed] [Google Scholar]
  20. Rajotte D., Sadowski H. B., Haman A., Gopalbhai K., Meloche S., Liu L., Krystal G., Hoang T. Contribution of both STAT and SRF/TCF to c-fos promoter activation by granulocyte-macrophage colony-stimulating factor. Blood. 1996 Oct 15;88(8):2906–2916. [PubMed] [Google Scholar]
  21. Rus H. G., Niculescu F., Shin M. L. Sublytic complement attack induces cell cycle in oligodendrocytes. J Immunol. 1996 Jun 15;156(12):4892–4900. [PubMed] [Google Scholar]
  22. Saatcioglu F., Claret F. X., Karin M. Negative transcriptional regulation by nuclear receptors. Semin Cancer Biol. 1994 Oct;5(5):347–359. [PubMed] [Google Scholar]
  23. Sher E. R., Leung D. Y., Surs W., Kam J. C., Zieg G., Kamada A. K., Szefler S. J. Steroid-resistant asthma. Cellular mechanisms contributing to inadequate response to glucocorticoid therapy. J Clin Invest. 1994 Jan;93(1):33–39. doi: 10.1172/JCI116963. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Staynov D. Z., Lee T. H. Expression of interleukin-5 and granulocyte-macrophage colony-stimulating factor in human peripheral blood mononuclear cells after activation with phorbol myristate acetate. Immunology. 1992 Jan;75(1):196–201. [PMC free article] [PubMed] [Google Scholar]
  25. Takeshita A., Chen Y., Watanabe A., Kitano S., Hanazawa S. TGF-beta induces expression of monocyte chemoattractant JE/monocyte chemoattractant protein 1 via transcriptional factor AP-1 induced by protein kinase in osteoblastic cells. J Immunol. 1995 Jul 1;155(1):419–426. [PubMed] [Google Scholar]
  26. Treisman R. Regulation of transcription by MAP kinase cascades. Curr Opin Cell Biol. 1996 Apr;8(2):205–215. doi: 10.1016/s0955-0674(96)80067-6. [DOI] [PubMed] [Google Scholar]
  27. Wang C. Y., Bassuk A. G., Boise L. H., Thompson C. B., Bravo R., Leiden J. M. Activation of the granulocyte-macrophage colony-stimulating factor promoter in T cells requires cooperative binding of Elf-1 and AP-1 transcription factors. Mol Cell Biol. 1994 Feb;14(2):1153–1159. doi: 10.1128/mcb.14.2.1153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Webster K. A., Discher D. J., Bishopric N. H. Induction and nuclear accumulation of fos and jun proto-oncogenes in hypoxic cardiac myocytes. J Biol Chem. 1993 Aug 5;268(22):16852–16858. [PubMed] [Google Scholar]
  29. Yang-Yen H. F., Chambard J. C., Sun Y. L., Smeal T., Schmidt T. J., Drouin J., Karin M. Transcriptional interference between c-Jun and the glucocorticoid receptor: mutual inhibition of DNA binding due to direct protein-protein interaction. Cell. 1990 Sep 21;62(6):1205–1215. doi: 10.1016/0092-8674(90)90396-v. [DOI] [PubMed] [Google Scholar]
  30. Yu K., Lu D., Paddy M. R., Lenk S. E., Raizada M. K. Angiotensin II regulation of plasminogen activator inhibitor-1 gene expression in neurons of normotensive and spontaneously hypertensive rat brains. Endocrinology. 1996 Jun;137(6):2503–2513. doi: 10.1210/endo.137.6.8641204. [DOI] [PubMed] [Google Scholar]
  31. Zawaski K., Gruebele A., Kaplan D., Reddy S., Mortensen A., Novak R. F. Evidence for enhanced expression of c-fos, c-jun, and the Ca(2+)-activated neutral protease in rat liver following carbon tetrachloride administration. Biochem Biophys Res Commun. 1993 Dec 15;197(2):585–590. doi: 10.1006/bbrc.1993.2519. [DOI] [PubMed] [Google Scholar]
  32. de Groot R. P., van Dijk T. B., Caldenhoven E., Coffer P. J., Raaijmakers J. A., Lammers J. W., Koenderman L. Activation of 12-O-tetradecanoylphorbol-13-acetate response element- and dyad symmetry element-dependent transcription by interleukin-5 is mediated by Jun N-terminal kinase/stress-activated protein kinase kinases. J Biol Chem. 1997 Jan 24;272(4):2319–2325. doi: 10.1074/jbc.272.4.2319. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES