Skip to main content
PMC home page
Mediators of Inflammation logoLink to Mediators of Inflammation
. 2001 Jun;10(3):135–142. doi: 10.1080/09629350124155

Pro-inflammatory cytokines induce c-fos expression followed by IL-6 release in human airway smooth muscle cells.

S McKay 1, M M Bromhaar 1, J C de Jongste 1, H C Hoogsteden 1, P R Saxena 1, H S Sharma 1
PMCID: PMC1781705  PMID: 11545250

Abstract

BACKGROUND: Airway smooth muscle (ASM) is considered to be a target for mediators released during airway inflammation. AIMS: To investigate the expression of c-fos, a constituent of the transcription factor activator protein-1, in human ASM cells. In addition, to measure the release of interleukin (IL)-6 into the conditioned medium of stimulated ASM cells, as well as DNA biosynthesis and changes in cell number. METHODS: Serum-deprived human ASM cells in the G0/G1 phase were stimulated with the pro-inflammatory cytokines; tumour necrosis factor-alpha, IL-1beta, IL-5 and IL-6. The expression of mRNA encoding the proto-oncogene c-fos was measured by Northern blot analysis. Cell proliferation was assessed by [3H]-thymidine incorporation assays and cell counting, and IL-6 levels in cell-conditioned medium were measured by enzyme-linked immunosorbent assay. RESULTS: All of the cytokines investigated induced a rapid (within 1 h) and transient increase in the expression of mRNA encoding c-fos, followed by the expression and enhanced release of IL-6. Cell proliferation remained unchanged in cytokine-stimulated cells. CONCLUSIONS: Cytokine-induced c-fos expression in human ASM cells could be described as a marker of cell 'activation'. The possible association of these results with airway inflammation, through secondary intracellular mechanisms such as cytokine production, is discussed.

Full Text

The Full Text of this article is available as a PDF (226.3 KB).

Selected References

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

  1. Amrani Y., Panettieri R. A., Jr, Frossard N., Bronner C. Activation of the TNF alpha-p55 receptor induces myocyte proliferation and modulates agonist-evoked calcium transients in cultured human tracheal smooth muscle cells. Am J Respir Cell Mol Biol. 1996 Jul;15(1):55–63. doi: 10.1165/ajrcmb.15.1.8679222. [DOI] [PubMed] [Google Scholar]
  2. Borish L., Mascali J. J., Dishuck J., Beam W. R., Martin R. J., Rosenwasser L. J. Detection of alveolar macrophage-derived IL-1 beta in asthma. Inhibition with corticosteroids. J Immunol. 1992 Nov 1;149(9):3078–3082. [PubMed] [Google Scholar]
  3. Broide D. H., Lotz M., Cuomo A. J., Coburn D. A., Federman E. C., Wasserman S. I. Cytokines in symptomatic asthma airways. J Allergy Clin Immunol. 1992 May;89(5):958–967. doi: 10.1016/0091-6749(92)90218-q. [DOI] [PubMed] [Google Scholar]
  4. De S., Zelazny E. T., Souhrada J. F., Souhrada M. IL-1 beta and IL-6 induce hyperplasia and hypertrophy of cultured guinea pig airway smooth muscle cells. J Appl Physiol (1985) 1995 Apr;78(4):1555–1563. doi: 10.1152/jappl.1995.78.4.1555. [DOI] [PubMed] [Google Scholar]
  5. DiCosmo B. F., Geba G. P., Picarella D., Elias J. A., Rankin J. A., Stripp B. R., Whitsett J. A., Flavell R. A. Airway epithelial cell expression of interleukin-6 in transgenic mice. Uncoupling of airway inflammation and bronchial hyperreactivity. J Clin Invest. 1994 Nov;94(5):2028–2035. doi: 10.1172/JCI117556. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Ebina M., Takahashi T., Chiba T., Motomiya M. Cellular hypertrophy and hyperplasia of airway smooth muscles underlying bronchial asthma. A 3-D morphometric study. Am Rev Respir Dis. 1993 Sep;148(3):720–726. doi: 10.1164/ajrccm/148.3.720. [DOI] [PubMed] [Google Scholar]
  7. Ediger T. L., Toews M. L. Synergistic stimulation of airway smooth muscle cell mitogenesis. J Pharmacol Exp Ther. 2000 Sep;294(3):1076–1082. [PubMed] [Google Scholar]
  8. Ghaffar O., Hamid Q., Renzi P. M., Allakhverdi Z., Molet S., Hogg J. C., Shore S. A., Luster A. D., Lamkhioued B. Constitutive and cytokine-stimulated expression of eotaxin by human airway smooth muscle cells. Am J Respir Crit Care Med. 1999 Jun;159(6):1933–1942. doi: 10.1164/ajrccm.159.6.9805039. [DOI] [PubMed] [Google Scholar]
  9. Glassberg M. K., Ergul A., Wanner A., Puett D. Endothelin-1 promotes mitogenesis in airway smooth muscle cells. Am J Respir Cell Mol Biol. 1994 Mar;10(3):316–321. doi: 10.1165/ajrcmb.10.3.7509612. [DOI] [PubMed] [Google Scholar]
  10. Hakonarson H., Maskeri N., Carter C., Grunstein M. M. Regulation of TH1- and TH2-type cytokine expression and action in atopic asthmatic sensitized airway smooth muscle. J Clin Invest. 1999 Apr;103(7):1077–1087. doi: 10.1172/JCI5809. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hallsworth M. P., Soh C. P., Twort C. H., Lee T. H., Hirst S. J. Cultured human airway smooth muscle cells stimulated by interleukin-1beta enhance eosinophil survival. Am J Respir Cell Mol Biol. 1998 Dec;19(6):910–919. doi: 10.1165/ajrcmb.19.6.3275. [DOI] [PubMed] [Google Scholar]
  12. Hedges J. C., Singer C. A., Gerthoffer W. T. Mitogen-activated protein kinases regulate cytokine gene expression in human airway myocytes. Am J Respir Cell Mol Biol. 2000 Jul;23(1):86–94. doi: 10.1165/ajrcmb.23.1.4014. [DOI] [PubMed] [Google Scholar]
  13. Jeffery P. K. Morphology of the airway wall in asthma and in chronic obstructive pulmonary disease. Am Rev Respir Dis. 1991 May;143(5 Pt 1):1152–1161. doi: 10.1164/ajrccm/143.5_Pt_1.1152. [DOI] [PubMed] [Google Scholar]
  14. Jiang B., Brecher P. N-Acetyl-L-cysteine potentiates interleukin-1beta induction of nitric oxide synthase : role of p44/42 mitogen-activated protein kinases. Hypertension. 2000 Apr;35(4):914–918. doi: 10.1161/01.hyp.35.4.914. [DOI] [PubMed] [Google Scholar]
  15. John M., Au B. T., Jose P. J., Lim S., Saunders M., Barnes P. J., Mitchell J. A., Belvisi M. G., Chung K. F. Expression and release of interleukin-8 by human airway smooth muscle cells: inhibition by Th-2 cytokines and corticosteroids. Am J Respir Cell Mol Biol. 1998 Jan;18(1):84–90. doi: 10.1165/ajrcmb.18.1.2813. [DOI] [PubMed] [Google Scholar]
  16. John M., Hirst S. J., Jose P. J., Robichaud A., Berkman N., Witt C., Twort C. H., Barnes P. J., Chung K. F. Human airway smooth muscle cells express and release RANTES in response to T helper 1 cytokines: regulation by T helper 2 cytokines and corticosteroids. J Immunol. 1997 Feb 15;158(4):1841–1847. [PubMed] [Google Scholar]
  17. Karin M., Liu Z. g., Zandi E. AP-1 function and regulation. Curr Opin Cell Biol. 1997 Apr;9(2):240–246. doi: 10.1016/s0955-0674(97)80068-3. [DOI] [PubMed] [Google Scholar]
  18. Laporte J. D., Moore P. E., Lahiri T., Schwartzman I. N., Panettieri R. A., Jr, Shore S. A. p38 MAP kinase regulates IL-1 beta responses in cultured airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2000 Nov;279(5):L932–L941. doi: 10.1152/ajplung.2000.279.5.L932. [DOI] [PubMed] [Google Scholar]
  19. Lechin F., van der Dijs B., Orozco B., Lechin M., Lechin A. E. Increased levels of free serotonin in plasma of symptomatic asthmatic patients. Ann Allergy Asthma Immunol. 1996 Sep;77(3):245–253. doi: 10.1016/S1081-1206(10)63263-2. [DOI] [PubMed] [Google Scholar]
  20. Liu M. C., Bleecker E. R., Lichtenstein L. M., Kagey-Sobotka A., Niv Y., McLemore T. L., Permutt S., Proud D., Hubbard W. C. Evidence for elevated levels of histamine, prostaglandin D2, and other bronchoconstricting prostaglandins in the airways of subjects with mild asthma. Am Rev Respir Dis. 1990 Jul;142(1):126–132. doi: 10.1164/ajrccm/142.1.126. [DOI] [PubMed] [Google Scholar]
  21. Martin L. D., Rochelle L. G., Fischer B. M., Krunkosky T. M., Adler K. B. Airway epithelium as an effector of inflammation: molecular regulation of secondary mediators. Eur Respir J. 1997 Sep;10(9):2139–2146. doi: 10.1183/09031936.97.10092139. [DOI] [PubMed] [Google Scholar]
  22. McKay S., Hirst S. J., Haas M. B., de Jongste J. C., Hoogsteden H. C., Saxena P. R., Sharma H. S. Tumor necrosis factor-alpha enhances mRNA expression and secretion of interleukin-6 in cultured human airway smooth muscle cells. Am J Respir Cell Mol Biol. 2000 Jul;23(1):103–111. doi: 10.1165/ajrcmb.23.1.3765. [DOI] [PubMed] [Google Scholar]
  23. McKay S., de Jongste J. C., Saxena P. R., Sharma H. S. Angiotensin II induces hypertrophy of human airway smooth muscle cells: expression of transcription factors and transforming growth factor-beta1. Am J Respir Cell Mol Biol. 1998 Jun;18(6):823–833. doi: 10.1165/ajrcmb.18.6.2924. [DOI] [PubMed] [Google Scholar]
  24. Mitsunobu F., Mifune T., Hosaki Y., Ashida K., Yokota S., Tsugeno H., Tanizaki Y. Different roles of histamine and leukotriene C4 in the airways between patients with atopic and nonatopic asthma. J Asthma. 1998;35(4):367–372. doi: 10.3109/02770909809075670. [DOI] [PubMed] [Google Scholar]
  25. Muraguchi A., Hirano T., Tang B., Matsuda T., Horii Y., Nakajima K., Kishimoto T. The essential role of B cell stimulatory factor 2 (BSF-2/IL-6) for the terminal differentiation of B cells. J Exp Med. 1988 Feb 1;167(2):332–344. doi: 10.1084/jem.167.2.332. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Paulsson Y., Bywater M., Heldin C. H., Westermark B. Effects of epidermal growth factor and platelet-derived growth factor on c-fos and c-myc mRNA levels in normal human fibroblasts. Exp Cell Res. 1987 Jul;171(1):186–194. doi: 10.1016/0014-4827(87)90261-8. [DOI] [PubMed] [Google Scholar]
  27. Pompen M., Smids B. S., Dingemans K. P., Jansen H. M., Out T. A., Lutter R. Lung epithelial H292 cells induce differentiation of immature human HMC-1 mast cells by interleukin-6 and stem cell factor. Clin Exp Allergy. 2000 Aug;30(8):1104–1112. doi: 10.1046/j.1365-2222.2000.00881.x. [DOI] [PubMed] [Google Scholar]
  28. Pype J. L., Dupont L. J., Menten P., Van Coillie E., Opdenakker G., Van Damme J., Chung K. F., Demedts M. G., Verleden G. M. Expression of monocyte chemotactic protein (MCP)-1, MCP-2, and MCP-3 by human airway smooth-muscle cells. Modulation by corticosteroids and T-helper 2 cytokines. Am J Respir Cell Mol Biol. 1999 Oct;21(4):528–536. doi: 10.1165/ajrcmb.21.4.3660. [DOI] [PubMed] [Google Scholar]
  29. Redington A. E., Springall D. R., Ghatei M. A., Lau L. C., Bloom S. R., Holgate S. T., Polak J. M., Howarth P. H. Endothelin in bronchoalveolar lavage fluid and its relation to airflow obstruction in asthma. Am J Respir Crit Care Med. 1995 Apr;151(4):1034–1039. doi: 10.1164/ajrccm.151.4.7697227. [DOI] [PubMed] [Google Scholar]
  30. Sachinidis A., Schulte K., Ko Y., Meyer zu Brickwedde M. K., Hoppe V., Hoppe J., Vetter H. The induction of early response genes in rat smooth muscle cells by PDGF-AA is not sufficient to stimulate DNA-synthesis. FEBS Lett. 1993 Mar 22;319(3):221–224. doi: 10.1016/0014-5793(93)80550-e. [DOI] [PubMed] [Google Scholar]
  31. Shanley T. P., Foreback J. L., Remick D. G., Ulich T. R., Kunkel S. L., Ward P. A. Regulatory effects of interleukin-6 in immunoglobulin G immune-complex-induced lung injury. Am J Pathol. 1997 Jul;151(1):193–203. [PMC free article] [PubMed] [Google Scholar]
  32. Stewart A. G., Tomlinson P. R., Fernandes D. J., Wilson J. W., Harris T. Tumor necrosis factor alpha modulates mitogenic responses of human cultured airway smooth muscle. Am J Respir Cell Mol Biol. 1995 Jan;12(1):110–119. doi: 10.1165/ajrcmb.12.1.7529028. [DOI] [PubMed] [Google Scholar]
  33. Suter P. M., Suter S., Girardin E., Roux-Lombard P., Grau G. E., Dayer J. M. High bronchoalveolar levels of tumor necrosis factor and its inhibitors, interleukin-1, interferon, and elastase, in patients with adult respiratory distress syndrome after trauma, shock, or sepsis. Am Rev Respir Dis. 1992 May;145(5):1016–1022. doi: 10.1164/ajrccm/145.5.1016. [DOI] [PubMed] [Google Scholar]
  34. Sánchez-Guerrero I. M., Herrero N., Muro M., Vegara R. P., Campos M., García-Alonso A. M., Alvarez M. R. Co-stimulation of cultured peripheral blood mononuclear cells from intrinsic asthmatics with exogenous recombinant IL-6 produce high levels of IL-4-dependent IgE. Eur Respir J. 1997 Sep;10(9):2091–2096. doi: 10.1183/09031936.97.10092091. [DOI] [PubMed] [Google Scholar]
  35. Teran L. M., Carroll M. P., Shute J. K., Holgate S. T. Interleukin 5 release into asthmatic airways 4 and 24 hours after endobronchial allergen challenge: its relationship with eosinophil recruitment. Cytokine. 1999 Jul;11(7):518–522. doi: 10.1006/cyto.1998.0457. [DOI] [PubMed] [Google Scholar]
  36. Tilg H., Trehu E., Atkins M. B., Dinarello C. A., Mier J. W. Interleukin-6 (IL-6) as an anti-inflammatory cytokine: induction of circulating IL-1 receptor antagonist and soluble tumor necrosis factor receptor p55. Blood. 1994 Jan 1;83(1):113–118. [PubMed] [Google Scholar]
  37. Wang J., Homer R. J., Chen Q., Elias J. A. Endogenous and exogenous IL-6 inhibit aeroallergen-induced Th2 inflammation. J Immunol. 2000 Oct 1;165(7):4051–4061. doi: 10.4049/jimmunol.165.7.4051. [DOI] [PubMed] [Google Scholar]
  38. Xing Z., Gauldie J., Cox G., Baumann H., Jordana M., Lei X. F., Achong M. K. IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. J Clin Invest. 1998 Jan 15;101(2):311–320. doi: 10.1172/JCI1368. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Mediators of Inflammation are provided here courtesy of Wiley

RESOURCES