Inflammation Research

, Volume 63, Issue 9, pp 769–778 | Cite as

Terpinen-4-ol and alpha-terpineol (tea tree oil components) inhibit the production of IL-1β, IL-6 and IL-10 on human macrophages

  • M. N. M. NogueiraEmail author
  • S. G. Aquino
  • C. Rossa Junior
  • D. M. P. Spolidorio
Original Research Paper



Tea tree oil (TTO) is an essential oil with anti-inflammatory properties, steam distilled from the plant Melaleuca alternifolia. We investigated the immunomodulatory properties of TTO and its components (terpinen-4-ol and alpha-terpineol) using lipopolysaccharide (LPS)-stimulated macrophages.


The ability of TTO, terpinen-4-ol and alpha-terpineol to modulate the macrophage response to bacterial LPS stimulation was assessed by ELISA for tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and IL-10 cytokine production and by western blotting for the activation of nuclear factor kappa B (NF-κB) and p38 mitogen-activated protein kinase (MAPK) signaling, which are associated with the expression of pro-inflammatory cytokines. We used a human monocytic cell line (U937) differentiated into macrophages.


LPS induced the production of all cytokines, and TTO and its components significantly reduced the production of IL-1β, IL-6 and IL-10. The production of TNF-α was not affected by either TTO or its major components. The modulation of cytokine production was not mediated by changes in NF-κB or p38 MAPK activation.


TTO, terpinen-4-ol and alpha-terpineol can suppress the production of inflammatory mediators in LPS-stimulated human macrophages; this inhibition was mediated by interfering with the NF-kB, p38 or ERK MAPK pathways.


Tea tree oil Macrophages Cytokines Inflammation 



This work was supported by grants from the Brazilian Federal Government through the National Council for Scientific and Technological Development (CNPq) and Coordination for Improvement of Higher Education Personnel (CAPES). This study was also supported by the State of São Paulo Research Foundation (FAPESP) (Grant number 2009/54190-0 and 2010/18968-3).


  1. 1.
    Carson CF, Hammer KA, Riley TV. Melaleuca alternifolia (Tea Tree) Oil: a review of antimicrobial and other medicinal properties. Clin Microbiol Rev. 2006;19:50–62.PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Cox SD, Mann CM, Markham JL. Interactions between components of the essential oil of Melaleuca alternifolia. J Appl Microbiol. 2001;91:492–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Keszei A, Hassan Y, Foley JW. A biochemical interpretation of terpene chemo types in Melaleuca alternifolia. J Chem Ecol. 2010;36:652–61.PubMedCrossRefGoogle Scholar
  4. 4.
    Shelton D, Zabaras D, Chohan S, Wyllie G, Baverstock P, Leach D, Henry R. Isolation and partial characterisation of a putative monoterpene synthase from Melaleuca alternifolia. Plant Physiol Biochem. 2004;42:875–82.PubMedGoogle Scholar
  5. 5.
    Catalán A, Pacheco JG, Martínez A, Mondaca MA. In vitro and in vivo activity of Melaleuca alternifolia mixed with tissue conditioner on Candida albicans. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008;105:327–32.PubMedCrossRefGoogle Scholar
  6. 6.
    Kwiecinski J, Eick S, Wójcik K. Effects of tea tree (Melaleuca alternifolia) oil on Staphylococcus aureus in biofilms and stationary growth phase. Int J Antimicrob Agents. 2009;33:343–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Minami M, Kita M, Nakaya T, Yamamoto T, Kuriyama H, Imanishi J, Minami M. The inhibitory effect of essential oils on herpes simplex virus type-1 replication in vitro. Microbiol Immunol. 2003;47:681–4.PubMedCrossRefGoogle Scholar
  8. 8.
    Wilkinson JM, Cavanagh HMA. Antibacterial activity of essential oils from Australian native plants. Phytother Res. 2005;19:643–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Greay SJ, Ireland DJ, Kissick HTA, Levy MW, Beilharz TV, Riley CF, Carson CF. Induction of necrosis and cell cycle arrest in murine cancer cell lines by Melaleuca alternifolia (tea tree) oil and terpinen-4-ol. Cancer Chemother Pharmacol. 2010;65:877–88.PubMedCrossRefGoogle Scholar
  10. 10.
    Hart PH, Brand C, Carson CF, Riley TV, Prager RH, Finlay-Jones JJ. Terpinen-4-ol, the main component of the essential oil of Melaleuca alternifolia (tea tree oil), suppresses inflammatory mediator production by activated human monocytes. Inflamm Res. 2000;49:619–26.PubMedCrossRefGoogle Scholar
  11. 11.
    Bassett IB, Pannowitz DL, Barnetson RS. A comparative study of tea-tree oil versus benzoylperoxide in the treatment of acne. Med J Aust. 1990;153:455–8.PubMedGoogle Scholar
  12. 12.
    Carson CF, Ashton L, Dry L, Smith DW, Riley TV. Melaleuca alternifolia (tea tree) oil gel (6%) for the treatment of recurrent herpes labialis. J Antimicrob Chemother. 2001;48:450–1.PubMedCrossRefGoogle Scholar
  13. 13.
    Soukoulis S, Hirsch R. The effects of a tea tree oil-containing gel on plaque and chronic gingivitis. Aust Dent J. 2004;49:78–83.PubMedCrossRefGoogle Scholar
  14. 14.
    Khalil Z, Pearce AL, Satkunanathan N, Storer E, Finlay-Jones JJ, Hart PH. Regulation of wheal and flare by tea tree oil: complementary human and rodent studies. J Invest Dermatol. 2004;123:683–90.PubMedCrossRefGoogle Scholar
  15. 15.
    Caldefie-Chézet F, Fusillier C, Jarde T, Laroye H, Damez M, Vasson MP, Guillot J. Potential anti-inflammatory effects of Melaleuca alternifolia essential oil on human peripheral blood leukocytes. Phytother Res. 2006;20:364–70.PubMedCrossRefGoogle Scholar
  16. 16.
    Brand C, Townley SL, Finlay-Jones JJ, Hart PH. Tea tree oil reduces histamine-induced edema in murine ears. Inflamm Res. 2002;51:283–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Abe S, Maruyama N, Hayama K, Ishibashi H, Inoue S, Oshima H, Yamaguchi H. Suppression of tumor necrosis factor-alpha-induced neutrophil adherence responses by essential oils. Mediators Inflamm. 2003;12:323–8.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Eskan MA, Rose BG, Benakanakere MR, Zeng Q, Fujioka D, Martin MH, Lee MJ, Kinane DF. TLR4 and S1P receptors cooperate to enhance inflammatory cytokine production in human gingival epithelial cells. Eur J Immunol. 2008;38:1138–47.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Souza JA, Rossa C Jr, Garlet GP, Nogueira AV, Cirelli JA. Modulation of host cell signaling pathways as a therapeutic approach in periodontal disease. J Appl Oral Sci. 2012;20:128–38.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Luvizotto-Santos R, Cordeiro PJM, Vieira EM. Analysis of methyl parathion in tilapia filets using a simple solid phase extraction clean-up and GC-NPD. Braz J Food Technol. 2009;7:158–61.Google Scholar
  21. 21.
    Sciarronea D, Ragonesea C, Carnovalea C, Pipernoa A, Dugoa P, Dugoa G, Mondello L. Evaluation of tea tree oil quality and ascaridole: a deep study by means of chiral and multi heart-cuts multidimensional gas chromatography system coupled to mass spectrometry detection. J Chromatogr. 2010;1217:6422–7.CrossRefGoogle Scholar
  22. 22.
    Kikkert R, Laine ML, Aarden LA, Van Winkelhoff AJ. Activation of toll-like receptors 2 and 4 by gram-negative periodontal bacteria. Oral Microbiol Immunol. 2007;22:145–51.PubMedCrossRefGoogle Scholar
  23. 23.
    Rovera G, Santoli D, Damsky C. Human promyelocytic leukemia cells in culture differentiate into macrophage-like cells when treated with a phorbol diester. Proc Nati Acad Sci. 1979;76:2779–83.CrossRefGoogle Scholar
  24. 24.
    Medzhitov R. Toll like receptors and innate immunity. Nat Rev Immunol. 2001;1:135–45.PubMedGoogle Scholar
  25. 25.
    Feldman M, Grenier D. Cranberry proanthocyanidins act in synergy with licochalcone A to reduce Porphyromonas gingivalis growth and virulence properties, and to suppress cytokine secretion by macrophages. J Appl Microbiol. 2012;113:438–47.PubMedCrossRefGoogle Scholar
  26. 26.
    Bradford MM. Rapid and sensitive method for the quantification of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248–54.PubMedCrossRefGoogle Scholar
  27. 27.
    Brand C, Ferrante A, Prager RH, Riley TV, Carson CF, Finlay-Jones JJ, Hart PH. The water-soluble components of the essential oil of Melaleuca Alternifólia (tea tree oil) suppress the production of superoxide by human monocytes, but not neutrophils, activated in vitro. Inflamm Res. 2001;50:213–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Jain S, Darveau RP. Contribution of Porphyromonas gingivalis lipopolysaccharide to periodontitis. Periodontology. 2000;2010(54):53–70.Google Scholar
  29. 29.
    Shirakawa F, Mizel SB. In vitro activation and nuclear translocation of NF-kappaB catalyzed by cyclic AMP-dependent protein kinase and protein kinase C. Mol Cell Biol. 1989;9:2424–30.PubMedCentralPubMedGoogle Scholar
  30. 30.
    Traenckner EB, Pahl HL, Henkel T, Schmidt KN, Wilk S. Baeuerle, P.A. Phosphorylation of human IkappaB-alpha on serines 32 and 36 controls IkappaB-alpha proteolysis and NF-kappaB activation in response to diverse stimuli. EMBO J. 1995;14:2876–83.PubMedCentralPubMedGoogle Scholar
  31. 31.
    Lu YC, Yeh WC, Ohashi OS. LPS/TLR4 signal transduction pathway. Cytokine. 2008;42:145–51.PubMedCrossRefGoogle Scholar
  32. 32.
    Brand C, Grimbaldeston MA, Gam-ble JR, Drew J, Finlay-Jones JJ, Hart PH. Tea tree oil reduces the swelling associated with the efferent phase of a contact hypersensitivity response. Inflamm Res. 2002;51:236–44.PubMedCrossRefGoogle Scholar
  33. 33.
    Pearce AL, Finlay-Jones JJ, Hart PH. Reduction of nickel-induced contact hypersensitivity reactions by topical tea tree oil in humans. Inflamm Res. 2005;54:22–30.PubMedCrossRefGoogle Scholar
  34. 34.
    Koh KJ, Earce AL, Marsh-man G, Finlay-Jones JJ, Hart PH. Tea tree oil reduces histamine-induced skin inflammation. Br J Dermatol. 2002;147:1212–7.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel 2014

Authors and Affiliations

  • M. N. M. Nogueira
    • 1
    • 2
    Email author
  • S. G. Aquino
    • 1
  • C. Rossa Junior
    • 1
  • D. M. P. Spolidorio
    • 3
  1. 1.Department of Diagnosis and SurgerySchool of Dentistry Araraquara, UNESPAraraquaraBrazil
  2. 2.Sao PauloBrazil
  3. 3.Department of Physiology and PathologySchool of Dentistry Araraquara, UNESPAraraquaraBrazil

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