Skip to main content

Advertisement

SpringerLink
Log in

Tetracyclines and Chemically Modified Tetracycline-3 (CMT-3) Modulate Cytokine Secretion by Lipopolysaccharide-Stimulated Whole Blood

  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

In addition to their bacteriostatic effect, tetracyclines, which are often used in the treatment of periodontitis, also present anti-inflammatory properties. In the present study, we investigated the effects of tetracycline (TC), doxycycline (doxy), and chemically modified tetracycline-3 (CMT-3) on the production of pro-inflammatory mediators and matrix metalloproteinases (MMPs) in an ex vivo human whole blood (WB) model stimulated with Porphyromonas gingivalis lipopolysaccharide (LPS). WB samples obtained from three periodontitis patients and six healthy subjects were stimulated with P. gingivalis LPS in the absence and presence of TC, doxy, or CMT-3. The secretion of interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), MMP-8, and MMP-9 by the WB samples was determined using enzyme-linked immunosorbent assays. P. gingivalis LPS significantly increased the secretion of all cytokines and MMPs tested. While we observed inter-patient variations, TC, doxy, and CMT-3 caused reductions of LPS-induced cytokine secretion to various degrees. TC, doxy, and CMT-3 had no significant effect on MMP-8 and MMP-9 secretion by LPS-stimulated WB samples. In conclusion, we used a human WB model that takes into consideration relevant in vivo immune cell interactions in the presence of plasma proteins to show that TC, doxy, and CMT-3 can reduce the production of pro-inflammatory mediators. This property may contribute to the clinically proven benefits of these molecules in the treatment of periodontitis and other chronic inflammatory diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Kornman, K. S., R. C. Page, and M. S. Tonetti. 1997. The host response to the microbial challenge in periodontitis: assembling the players. Periodontol 2000 14:33–53. doi:10.1111/j.1600-0757.1997.tb00191.x.

    Article  PubMed  CAS  Google Scholar 

  2. Ebersole, J. L., and M. Taubman. 1994. The protective nature of host responses in periodontal diseases. Periodontol 2000 5:112–141. doi:10.1111/j.1600-0757.1994.tb00021.x.

    Article  PubMed  CAS  Google Scholar 

  3. Okada, H., and S. Murakami. 1998. Cytokine expression in periodontal health and disease. Crit. Rev. Oral Biol. Med. 9:248–266. doi:10.1177/10454411980090030101.

    Article  PubMed  CAS  Google Scholar 

  4. Birkedal-Hansen, H. 1993. Role of cytokines and inflammatory mediators in tissue destruction. J. Periodontal. Res. 28:500–510. doi:10.1111/j.1600-0765.1993.tb02113.x.

    Article  PubMed  CAS  Google Scholar 

  5. Sorsa, T., L. Tjäderhane, Y. T. Konttinen, et al. 2006. Matrix metalloproteinases: contribution to pathogenesis, diagnosis and treatment of periodontal inflammation. Ann. Med. 38:306–321. doi:10.1080/07853890600800103.

    Article  PubMed  CAS  Google Scholar 

  6. Socransky, S. S., A. D. Haffajee, M. A. Gugini, C. Smith, and R. L. Kent. 1998. Microbial complexes in subgingival plaque. J. Periodontol. 25:134–144. doi:10.1111/j.1600-051X.1998.tb02419.x.

    Article  CAS  Google Scholar 

  7. Bodet, C., F. Chandad, and D. Grenier. 2006. Anti-inflammatory activity of a high-molecular-weight cranberry fraction on macrophages stimulated by lipopolysaccharides from periodontopathogens. J. Dent. Res. 85:235–239. doi:10.1177/154405910608500306.

    Article  PubMed  CAS  Google Scholar 

  8. Bodet, C., F. Chandad, and D. Grenier. 2007. Cranberry components inhibit interleukin-6, interleukin-8, and prostaglandin E2 production by lipopolysaccharide-activated gingival fibroblasts. Eur. J. Oral Sci. 115:64–70. doi:10.1111/j.1600-0722.2007.00415.x.

    Article  PubMed  CAS  Google Scholar 

  9. Bodet, C., E. Andrian, S. I. Tanabe, and D. Grenier. 2007. Actinobacillus actinomycetemcomitans lipopolysaccharide regulates matrix metalloproteinase, tissue inhibitors of matrix metalloproteinase, and plasminogen activator production by human gingival fibroblasts: a potential role in connective tissue destruction. J. Cell Physiol. 212:189–194. doi:10.1002/jcp.21018.

    Article  PubMed  CAS  Google Scholar 

  10. Bodet, C., F. Chandad, and D. Grenier. 2005. Porphyromonas gingivalis-induced inflammatory mediator profile in an ex vivo human whole blood model. Clin. Exp. Immunol. 143:50–57. doi:10.1111/j.1365-2249.2005.02956.x.

    Article  Google Scholar 

  11. Bidault, P., F. Chandad, and D. Grenier. 2007. Systemic antibiotic therapy in the treatment of periodontitis. J. Can. Dent. Assoc. 73:515–520.

    PubMed  Google Scholar 

  12. Seymour, R., and P. A. Heasman. 1995. Tetracyclines in the management of periodontal diseases. J. Clin. Periodontol. 22:22–35.

    PubMed  CAS  Google Scholar 

  13. Sapadin, A. N., and R. Fleischmajer. 2006. Tetracyclines: Nonantibiotic properties and their clinical implications. J. Am. Acad. Dermatol. 54:258–265. doi:10.1016/j.jaad.2005.10.004.

    Article  PubMed  Google Scholar 

  14. Golub, L. M., H. M. Lee, M. E. Ryan, W. V. Giannobile, J. Payne, and T. Sorsa. 1998. Tetracyclines inhibit connective tissue breakdown by multiple non-antimicrobial mechanisms. Adv. Dent. Res. 12:12–26. doi:10.1177/08959374980120010501.

    Article  PubMed  CAS  Google Scholar 

  15. Sorsa, T., L. Tjäderhane, and T. Salo. 2004. Matrix metalloproteinases (MMPs) in oral diseases. Oral Dis. 10:311–318. doi:10.1111/j.1601-0825.2004.01038.x.

    Article  PubMed  CAS  Google Scholar 

  16. Gabler, W. L., and H. R. Creamer. 1991. Suppression of human neutrophil functions by tetracycline. J. Periodontal. Res. 26:52–58. doi:10.1111/j.1600-0765.1991.tb01626.x.

    Article  PubMed  CAS  Google Scholar 

  17. Golub, L. M., N. S. Ramamurthy, T. F. McNamara, R. A. Greenwald, and R. R. Rifkin. 1991. Tetracyclines inhibit connective tissue breakdown: new therapeutic implications for an old family of drugs. Crit. Rev. Oral Biol. Med. 2:297–321.

    PubMed  CAS  Google Scholar 

  18. Lokeshwar, B. L., M. G. Selzer, B. Q. Zhu, N. L. Block, and L. M. Golub. 2002. Inhibition of cell proliferation, invasion, tumor growth and metastasis by an oral nonantimicrobial tetracycline analog (COL-3) in a metastatic prostate cancer model. Int. J. Cancer 98:297–302. doi:10.1002/ijc.10168.

    Article  PubMed  CAS  Google Scholar 

  19. Darveau, R. P., and R. E. Hancock. 1983. Procedure for isolation of bacterial lipopolysaccharides from both smooth and rough Pseudomonas aeruginosa and Salmonella typhimurium strains. J. Bacteriol. 155:831–838.

    PubMed  CAS  Google Scholar 

  20. Patel, R. N., M. G. Attur, M. N. Dave, et al. 1999. A novel mechanism of action of chemically modified tetracyclines: inhibition of COX-2-mediated prostaglandin E2 production. J. Immunol. 163:3459–3467.

    PubMed  CAS  Google Scholar 

  21. Hoyt, J. C., J. Ballering, H. Numanami, J. M. Hayden, and R. A. Robbins. 2006. Doxycycline modulates nitric oxide production in murine lung epithelial cells. J. Immunol. 176:567–572.

    PubMed  CAS  Google Scholar 

  22. Pruzanski, W., E. Stefanski, P. Vadas, T. F. McNamara, N. Ramamurthy, and L. M. Golub. 1998. Chemically modified non-antimicrobial tetracyclines inhibit activity of phospholipases A2. J. Rheumatol. 25:1807–1812.

    PubMed  CAS  Google Scholar 

  23. Cazalis, J., C. Bodet, G. Gagnon, and D. Grenier. 2008. Doxycycline reduces lipopolysaccharide-induced inflammatory mediator secretion in macrophage and ex vivo human whole blood models. J. Periodontol. 79:1762–1768. doi:10.1902/jop.2008.080051.

    Article  PubMed  CAS  Google Scholar 

  24. Kinane, D. F., and T. C. Hart. 2003. Genes and gene polymorphisms associated with periodontal disease. Crit. Rev. Oral Biol. Med. 14:430–449. doi:10.1177/154411130301400605.

    Article  PubMed  CAS  Google Scholar 

  25. Graves, D. T., and D. Cochran. 2003. The contribution of interleukin-1 and tumor necrosis factor to periodontal tissue destruction. J. Periodontol. 74:391–401. doi:10.1902/jop.2003.74.3.391.

    Article  PubMed  CAS  Google Scholar 

  26. Assuma, R., T. Oates, D. Cochran, S. Amar, and D. T. Graves. 1998. IL-1 and TNF antagonists inhibit the inflammatory response and bone loss in experimental periodontitis. J. Immunol. 160:403–409.

    PubMed  CAS  Google Scholar 

  27. Takahashi, K., S. Takashiba, A. Nagai, et al. 1994. Assessment of interleukin-6 in the pathogenesis of periodontal disease. J. Periodontol. 65:147–153.

    PubMed  CAS  Google Scholar 

  28. Kudo, O., A. Sabokbar, A. Pocock, I. Itonaga, Y. Fujikawa, and N. A. Athanasou. 2003. Interleukin-6 and interleukin-11 support human osteoclast formation by a RANKL-independent mechanism. Bone 32:1–7. doi:10.1016/S8756–3282(02)00915–8.

    Article  PubMed  CAS  Google Scholar 

  29. Kusano, K., C. Miyaura, M. Inada, et al. 1998. Regulation of matrix metalloproteinases (MMP-2, -3, -9, and -13) by interleukin-1 and interleukin-6 in mouse calvaria: association of MMP induction with bone resorption. Endocrinology 139:1338–1345. doi:10.1210/en.139.3.1338.

    Article  PubMed  CAS  Google Scholar 

  30. Jin, L. J., W. K. Leung, E. F. Corbet, and B. Soder. 2002. Relationship of changes in interleukin-8 levels and granulocyte elastase activity in gingival crevicular fluid to subgingival periodontopathogens following non-surgical periodontal therapy in subjects with chronic periodontitis. J. Clin. Periodontol. 29:604–614. doi:10.1034/j.1600-051X.2002.290704.x.

    Article  PubMed  CAS  Google Scholar 

  31. Gamonal, J., A. Acevedo, A. Bascones, O. Jorge, and A. Silva. 2001. Characterization of cellular infiltrate, detection of chemokine receptor CCR5 and interleukin-8 and RANTES chemokines in adult periodontitis. J. Periodontal. Res. 36:194–203. doi:10.1034/j.1600-0765.2001.360309.x.

    Article  PubMed  CAS  Google Scholar 

  32. Greenwaldm, R. A., L. M. Golub, N. S. Ramamurthy, M. Chowdhury, S. A. Moak, and T. Sorsa. 1998. In vitro sensitivity of the three mammalian collagenases to tetracycline inhibition: relationship to bone and cartilage degradation. Bone 22:33–38. doi:10.1016/S8756-3282(97)00221-4.

    Article  Google Scholar 

  33. Hanemaaijer, R., T. Sorsa, Y. T. Konttinen, et al. 1997. Matrix metalloproteinase-8 is expressed in rheumatoid synovial fibroblasts and endothelial cells. J. Biol. Chem. 272:31054–31059. doi:10.1074/jbc.272.50.31504.

    Article  Google Scholar 

  34. Sakellari, D., J. M. Goodson, S. S. Socransky, A. Kolokotronis, and A. Konstantinidis. 2000. Concentration of 3 tetracyclines in plasma, gingival crevice fluid and saliva. J. Clin. Periodontol. 27:53–60. doi:10.1034/j.1600-051x.2000.027001053.x.

    Article  PubMed  CAS  Google Scholar 

  35. Thomas, J., C. Walker, and M. Bradshaw. 2000. Long-term use of subantimicrobial dose doxycycline does not lead to changes in antimicrobial susceptibility. J. Periodontol. 71:1472–1483. doi:10.1902/jop.2000.71.9.1472.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by funding from the Canadian Institutes of Health Research. We would like to thank Charles Bodet for his technical assistance and invaluable editorial input.

Author information

Authors and Affiliations

  1. Groupe de Recherche en Écologie Buccale, Faculté de Médecine Dentaire, Université Laval, Quebec City, Quebec, G1K 7P4, Canada

    Julia Cazalis, Shin-ichi Tanabe, Guy Gagnon & Daniel Grenier

  2. Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Helsinki, Finland

    Timo Sorsa

  3. Cell Biology of Oral Diseases, Institute of Dentistry, University of Helsinki, Helsinki, Finland

    Timo Sorsa

Authors
  1. Julia Cazalis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shin-ichi Tanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guy Gagnon
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Timo Sorsa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Daniel Grenier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daniel Grenier.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cazalis, J., Tanabe, Si., Gagnon, G. et al. Tetracyclines and Chemically Modified Tetracycline-3 (CMT-3) Modulate Cytokine Secretion by Lipopolysaccharide-Stimulated Whole Blood. Inflammation 32, 130–137 (2009). https://doi.org/10.1007/s10753-009-9111-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-009-9111-9

KEY WORDS

Search

Navigation