, Volume 32, Issue 3, pp 163–168 | Cite as

CCL18 Production is Decreased in Alveolar Macrophages from Cigarette Smokers

  • Florian Kollert
  • Corina Probst
  • Joachim Müller-Quernheim
  • Gernot Zissel
  • Antje PrasseEmail author


It is generally known that cigarette smoke alters the activation of alveolar macrophages (AM). CC Chemokine Ligand 18 (CCL18) is a marker of alternatively activated macrophages and is highly expressed in the lung. This study examines the influence of chronic cigarette smoking on the expression of CCL18 by AM. Bronchoalveolar lavage (BAL) and serum were obtained from ten smokers and 14 non-smokers. CCL18 protein concentrations were measured in serum and BAL fluid (BALF) as well as in supernatants from BAL-cells by enzyme-linked immunosorbent assay. In this study we show that the CCL18 production of BAL-cells from smokers was significantly decreased compared to BAL-cells from non-smokers. The BALF CCL18 protein concentration per macrophage cell count was significantly reduced in smokers. Furthermore, we show a decrease in CCL18 production from BAL-cells after stimulation with LPS. This decrease in CCL18 production was only shown in BAL-cells from non-smokers, which is probably due to chronic LPS exposure of smokers, resulting in LPS hypo-responsiveness. No statistically significant difference of CCL18 concentrations was found in BALF or serum of smokers versus non-smokers. CCL18 production by BAL-cells is down-regulated by chronic cigarette smoking and LPS contamination in cigarette smoke might be one factor involved. Thus this article gives further evidence that chronic cigarette smoking alters the phenotype of AM and that the M2 marker CCL18 is down-regulated in smokers macrophages.


alveolar macrophages (AM) bronchoalveolar lavage (BAL) CCL18 lipopolysaccharides (LPS) smoking 


  1. 1.
    Baumgartner, K. B., J. M. Samet, C. A. Stidley, T. V. Colby, and J. A. Waldron. 1997. Cigarette smoking: a risk factor for idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care. Med. 155(1):242–248.PubMedGoogle Scholar
  2. 2.
    Ezzati, M., and A. D. Lopez. 2003. Estimates of global mortality attributable to smoking in 2000. Lancet. 362(9387):847–852. doi: 10.1016/S0140-6736(03)14338-3.PubMedCrossRefGoogle Scholar
  3. 3.
    Girod, C. E., and T. E. King Jr. 2005. COPD: a dust-induced disease. Chest. 128(4):3055–3064. doi: 10.1378/chest.128.4.3055.PubMedCrossRefGoogle Scholar
  4. 4.
    Lopez, A. D., and C. C. Murray. 1998. The global burden of disease, 1990–2020. Nat Med. 4(11):1241–1243. doi: 10.1038/3218.PubMedCrossRefGoogle Scholar
  5. 5.
    Fraig, M., U. Shreesha, D. Savici, and A. L. Katzenstein. 2002. Respiratory bronchiolitis: a clinicopathologic study in current smokers, ex-smokers, and never-smokers. Am. J. Surg. Pathol. 26(5):647–653. doi: 10.1097/00000478-200205000-00011.PubMedCrossRefGoogle Scholar
  6. 6.
    Tetley, T. D. 2002. Macrophages and the pathogenesis of COPD. Chest. 121(Suppl 5):156S–159S. doi: 10.1378/chest.121.5_suppl.156S.PubMedCrossRefGoogle Scholar
  7. 7.
    Prasse, A., D. V. Pechkovsky, G. B. Toews, W. Jungraithmayr, F. Kollert, T. Goldmann, E. Vollmer, J. Muller-Quernheim, and G. Zissel. 2006. A vicious circle of alveolar macrophages and fibroblasts perpetuates pulmonary fibrosis via CCL18. Am. J. Respir. Crit. Care. Med. 173(7):781–792. doi: 10.1164/rccm.200509-1518OC.PubMedCrossRefGoogle Scholar
  8. 8.
    Prasse, A., D. V. Pechkovsky, G. B. Toews, M. Schafer, S. Eggeling, C. Ludwig, M. Germann, F. Kollert, G. Zissel, and J. Muller-Quernheim. 2007. CCL18 as an indicator of pulmonary fibrotic activity in idiopathic interstitial pneumonias and systemic sclerosis. Arthritis. Rheum. 56(5):1685–1693. doi: 10.1002/art.22559.PubMedCrossRefGoogle Scholar
  9. 9.
    Goerdt, S., O. Politz, K. Schledzewski, R. Birk, A. Gratchev, P. Guillot, N. Hakiy, C. D. Klemke, E. Dippel, V. Kodelja, and C. E. Orfanos. 1999. Alternative versus classical activation of macrophages. Pathobiology. 67(5–6):222–226. doi: 10.1159/000028096.PubMedCrossRefGoogle Scholar
  10. 10.
    Gordon, S. 2003. Alternative activation of macrophages. Nat. Rev. Immunol. 3(1):23–35. doi: 10.1038/nri978.PubMedCrossRefGoogle Scholar
  11. 11.
    Guan, P., A. H. Burghes, A. Cunningham, P. Lira, W. H. Brissette, K. Neote, and S. R. McColl. 1999. Genomic organization and biological characterization of the novel human CC chemokine DC-CK-1/PARC/MIP-4/SCYA18. Genomics. 56(3):296–302. doi: 10.1006/geno.1998.5635.PubMedCrossRefGoogle Scholar
  12. 12.
    Hieshima, K., T. Imai, M. Baba, K. Shoudai, K. Ishizuka, T. Nakagawa, J. Tsuruta, M. Takeya, Y. Sakaki, K. Takatsuki, R. Miura, G. Opdenakker, D. J. Van, O. Yoshie, and H. Nomiyama. 1997. A novel human CC chemokine PARC that is most homologous to macrophage-inflammatory protein-1 alpha/LD78 alpha and chemotactic for T lymphocytes, but not for monocytes. J Immunol. 159(3):1140–1149.PubMedGoogle Scholar
  13. 13.
    Kodelja, V., C. Muller, O. Politz, N. Hakij, C. E. Orfanos, and S. Goerdt. 1998. Alternative macrophage activation-associated CC-chemokine-1, a novel structural homologue of macrophage inflammatory protein-1 alpha with a Th2-associated expression pattern. J. Immunol. 160(3):1411–1418.PubMedGoogle Scholar
  14. 14.
    Mantovani, A., A. Sica, S. Sozzani, P. Allavena, A. Vecchi, and M. Locati. 2004. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 25(12):677–686. doi: 10.1016/ Scholar
  15. 15.
    Prasse, A., M. Germann, D. V. Pechkovsky, A. Markert, T. Verres, M. Stahl, I. Melchers, W. Luttmann, J. Muller-Quernheim, and G. Zissel. 2007. IL-10-producing monocytes differentiate to alternatively activated macrophages and are increased in atopic patients. J. Allergy. Clin. Immunol. 119(2):464–471. doi: 10.1016/j.jaci.2006.09.030.PubMedCrossRefGoogle Scholar
  16. 16.
    Prasse, A., C. Probst, E. Bargagli, G. Zissel, G. B. Toews, K. R. Flaherty, M. Olschewski, P. Rottoli, J. Muller-Quernheim. Serum CC–chemokine ligand 18 concentration predicts outcome in idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 2009 February 6.Google Scholar
  17. 17.
    Cottin, V., H. Nunes, P-Y. Brillet, P. Delaval, G. Devouassoux, I. Tillie-Leblonde, D. Israel-Biet, I. Court-Fortune, D. Valeyre, J-F. Cordier, and Groupe d’Etude et de Recherche sur les Maladies “Orphelines” Pulmonaires (GERM“O”P). 2005. Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity. Eur. Respir. J. 26:586–593.PubMedCrossRefGoogle Scholar
  18. 18.
    Woodruff, P. G., L. L. Koth, Y. H. Yang, M. W. Rodriguez, S. Favoreto, G. M. Dolganov, A. C. Paquet, and D. J. Erle. 2005. A distinctive alveolar macrophage activation state induced by cigarette smoking. Am. J. Respir. Crit. Care. Med. 172(11):1383–1392. doi: 10.1164/rccm.200505-686OC.PubMedCrossRefGoogle Scholar
  19. 19.
    Heguy, A., T. P. O'Connor, K. Luettich, S. Worgall, A. Cieciuch, B. G. Harvey, N. R. Hackett, and R. G. Crystal. 2006. Gene expression profiling of human alveolar macrophages of phenotypically normal smokers and nonsmokers reveals a previously unrecognized subset of genes modulated by cigarette smoking. J. Mol. Med. 84(4):318–328. doi: 10.1007/s00109-005-0008-2.PubMedCrossRefGoogle Scholar
  20. 20.
    Barnes, P. J. 2000. Mechanisms in COPD: differences from asthma. Chest. 117(Suppl 2):10S–14S. doi: 10.1378/chest.117.2_suppl.10S.PubMedCrossRefGoogle Scholar
  21. 21.
    Gauldie, J., M. Kolb, K. Ask, G. Martin, P. Bonniaud, and D. Warburton. 2006. Smad3 signaling involved in pulmonary fibrosis and emphysema. Proc. Am. Thorac. Soc. 3(8):696–702. doi: 10.1513/pats.200605-125SF.PubMedCrossRefGoogle Scholar
  22. 22.
    Atamas, S. P., I. G. Luzina, J. Choi, N. Tsymbalyuk, N. H. Carbonetti, I. S. Singh, M. Trojanowska, and S. A. Jimenez. 2003. White B. Pulmonary and activation-regulated chemokine stimulates collagen production in lung fibroblasts. Am. J. Respir. Cell. Mol. Biol. 29(6):743–749. doi: 10.1165/rcmb.2003-0078OC.PubMedCrossRefGoogle Scholar
  23. 23.
    Hasday, J. D., R. Bascom, J. J. Costa, T. Fitzgerald, and W. Dubin. 1999. Bacterial endotoxin is an active component of cigarette smoke. Chest. 115(3):829–835. doi: 10.1378/chest.115.3.829.PubMedCrossRefGoogle Scholar
  24. 24.
    Edwards, K., K. M. Braun, G. Evans, A. O. Sureka, and S. Fan. 1999. Mainstream and sidestream cigarette smoke condensates suppress macrophage responsiveness to interferon gamma. Hum. Exp. Toxicol. 18(4):233–240. doi: 10.1191/096032799678839978.PubMedCrossRefGoogle Scholar
  25. 25.
    Pivarcsi, A., M. Gombert, M. C. eu-Nosjean, A. Lauerma, R. Kubitza, S. Meller, J. Rieker, A. Muller, C. L. Da, A. Haahtela, E. Sonkoly, W. H. Fridman, H. Alenius, L. Kemeny, T. Ruzicka, A. Zlotnik, and B. Homey. 2004. CC chemokine ligand 18, an atopic dermatitis-associated and dendritic cell-derived chemokine, is regulated by staphylococcal products and allergen exposure. J. Immunol. 173(9):5810–5817.PubMedGoogle Scholar
  26. 26.
    Bingisser, R., R. Speich, A. Zollinger, E. Russi, and K. Frei. 2000. Interleukin-10 secretion by alveolar macrophages and monocytes in sarcoidosis. Respiration. 67(3):280–286. doi: 10.1159/000029511.PubMedCrossRefGoogle Scholar
  27. 27.
    Salez, L., V. Balloy, R. N. van, M. Lebastard, L. Touqui, F. X. McCormack, and M. Chignard. 2001. Surfactant protein A suppresses lipopolysaccharide-induced IL-10 production by murine macrophages. J. Immunol. 166(10):6376–6382.PubMedGoogle Scholar
  28. 28.
    Vulcano, M., S. Struyf, P. Scapini, M. Cassatella, S. Bernasconi, R. Bonecchi, A. Calleri, G. Penna, L. Adorini, W. Luini, A. Mantovani, D. J. Van, and S. Sozzani. 2003. Unique regulation of CCL18 production by maturing dendritic cells. J. Immunol. 170(7):3843–3849.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Florian Kollert
    • 1
  • Corina Probst
    • 1
  • Joachim Müller-Quernheim
    • 1
  • Gernot Zissel
    • 1
  • Antje Prasse
    • 1
    Email author
  1. 1.Department of Pneumology, Medical CenterAlbert-Ludwigs UniversityFreiburgGermany

Personalised recommendations