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Planta Med 2016; 82(15): 1341-1345
DOI: 10.1055/s-0042-107799
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Gamma-Terpinene Modulation of LPS-Stimulated Macrophages is Dependent on the PGE2/IL-10 Axis

Theresa R. Ramalho
1   Laboratory of Immunopharmacology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brasil
,
Luciano R. Filgueiras
1   Laboratory of Immunopharmacology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brasil
,
Maria Talita Pacheco de Oliveira
2   Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Rio de Janeiro, Brasil
,
Ana Luisa de Araujo Lima
3   Natural Synthetic and Bioactive Products Post-graduation Program, Health Sciences Center, Federal University of Paraíba, João Pessoa, Paraíba, Brasil
,
Claudio Roberto Bezerra-Santos
4   Laboratory of Immunopharmacology, Department de Physiology and Pathology, Federal University of Paraíba, João Pessoa, Paraíba, Brasil
,
Sonia Jancar
1   Laboratory of Immunopharmacology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brasil
,
Marcia Regina Piuvezam
3   Natural Synthetic and Bioactive Products Post-graduation Program, Health Sciences Center, Federal University of Paraíba, João Pessoa, Paraíba, Brasil
4   Laboratory of Immunopharmacology, Department de Physiology and Pathology, Federal University of Paraíba, João Pessoa, Paraíba, Brasil
› Author Affiliations
Further Information

Publication History

received 07 March 2016
revised 15 April 2016

accepted 18 April 2016

Publication Date:
25 May 2016 (online)

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Abstract

Gamma-terpinene is a monoterpene present in the essential oils of several plants, including those from the Eucalyptus genus. This molecule was recently described as anti-inflammatory and microbiocidal, but little is known about the mechanisms behind its effects. The aim of the present study was to investigate the effect of gamma-terpinene on the lipopolysaccharide-induced production of cytokines by murine peritoneal macrophages. Gamma-terpinene treatment was found to reduce the production of proinflammatory cytokines, such as interleukin-1β and interleukin-6, and enhance that of the anti-inflammatory cytokine interleukin-10. This was accompanied by increased levels of the enzyme cycloxygenase-2 and its product, the lipid mediator prostaglandin E2. Inhibition of cycloxygenase-2 with nimesulide abolished the potentiating effect of gamma-terpinene on interleukin-10 production. Moreover, nimesulide treatment also abrogated the inhibitory effect of gamma-terpinene on interleukin-1β and interleukin-6. Furthermore, in macrophages from mice deficient in the interleukin-10 gene, gamma-terpinene failed to inhibit interleukin-1β and interleukin-6 production. These results suggest that this monoterpene promotes the prostaglandin E2/interleukin-10 axis, which inhibits the production of these proinflammatory cytokines.

Key words

gamma-terpinene - macrophage - cycloxygenase-2 - prostaglandin E2
 

  • References

  • 1 Lima Mda S, Quintans-Júnior LJ, de Santana WA, Martis Kaneto C, Pereira Soares MB, Villareal CF. Anti-inflammatory effects of carvacrol: evidence for a key role of interleukin-10. Eur J Pharmacol 2013; 699: 112-117
    CrossrefPubMedGoogle Scholar
  • 2 Guimarães AG, Quintans JS, Quintans jr. LJ. Monoterpenes with analgesic activity – a systematic review. Phytother Res 2013; 27: 1-15
    CrossrefPubMedGoogle Scholar
  • 3 Siveen KS, Kuttan G. Thujone inhibits lung metastasis induced by B16 F-10 melanoma cells in C57BL/6 mice. Can J Physiol Pharmacol 2011; 89: 691-703
    CrossrefPubMedGoogle Scholar
  • 4 Djenane D, Yangüela J, Amrouche T, Boubrit S, Boussad N, Roncalés P. Chemical composition and antimicrobial effects of essential oils of Eucalyptus globulus, Myrtus communis and Satureja hortensis against Escherichia coli O157:H7 and Staphylococcus aureus in minced beef. Food Sci Technol Int 2011; 17: 505-515
    CrossrefPubMedGoogle Scholar
  • 5 Ramalho TR, Oliveira MT, Lima AL, Bezerra-Santos CR, Piuvezam MR. Gamma-terpinene modulates acute inflammatory response in mice. Planta Med 2015; 81: 1248-1254
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol 2005; 5: 953-964
    Google Scholar
  • 7 Fleming BD, Mosser DM. Regulatory macrophages: setting the threshold for therapy. Eur J Immunol 2011; 41: 2498-2502
    CrossrefPubMedGoogle Scholar
  • 8 Moore KW, de Waal Malefyt R, Coffman RL, OʼGarra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 2001; 19: 683-765
    CrossrefPubMedGoogle Scholar
  • 9 Saraiva M, OʼGarra A. The regulation of IL-10 production by immune cells. Nat Rev Immunol 2010; 10: 170-181
    CrossrefPubMedGoogle Scholar
  • 10 Murray PJ. The primary mechanism of the IL-10-regulated antiinflammatory response is to selectively inhibit transcription. Proc Natl Acad Sci U S A 2005; 102: 8686-8691
    CrossrefPubMedGoogle Scholar
  • 11 Kühn R, Löhler J, Rennick D, Rajewsky K, Müller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 1993; 75: 263-274
    CrossrefPubMedGoogle Scholar
  • 12 Zigmond E, Bernshtein B, Friedlander G, Walker CR, Yona S, Kim KW, Brenner O, Krauthgamer R, Varol C, Müller W, Jung S. Macrophage-restricted interleukin-10 receptor deficiency, but not IL-10 deficiency, causes severe spontaneous colitis. Immunity 2014; 40: 720-733
    CrossrefPubMedGoogle Scholar
  • 13 Finnegan A, Kaplan CD, Cao Y, Eibel H, Glant TT, Zhang J. Collagen-induced arthritis is exacerbated in IL-10-deficient mice. Arthritis Res Ther 2003; 5: R18-R24
    CrossrefPubMedGoogle Scholar
  • 14 Yang X, Wang S, Fan Y, Han X. IL-10 deficiency prevents IL-5 overproduction and eosinophilic inflammation in a murine model of asthma-like reaction. Eur J Immunol 2000; 30: 382-391
    CrossrefPubMedGoogle Scholar
  • 15 Asadullah K, Sterry W, Stephanek K, Jasulaitis D, Leupold M, Audring H, Volk HD, Döcke WD. IL-10 is a key cytokine in psoriasis. Proof of principle by IL-10 therapy: a new therapeutic approach. J Clin Invest 1998; 101: 783-794
    CrossrefPubMedGoogle Scholar
  • 16 Kim SH, Serezani CH, Okunishi K, Zaslona Z, Aronoff DM, Peters-Golden M. Distinct protein kinase A anchoring proteins direct prostaglandin E2 modulation of Toll-like receptor signaling in alveolar macrophages. J Biol Chem 2011; 286: 8875-8883
    CrossrefPubMedGoogle Scholar
  • 17 Balboa MA, Shirai Y, Gaietta G, Ellisman MH, Balsinde J, Dennis EA. Localization of group V phospholipase A2 in caveolin-enriched granules in activated P388D1 macrophage-like cells. J Biol Chem 2003; 278: 48059-48065
    CrossrefPubMedGoogle Scholar
  • 18 Serezani CH, Lewis C, Jancar S, Peters-Golden M. Leukotriene B4 amplifies NF-κB activation in mouse macrophages by reducing SOCS1 inhibition of MyD88 expression. J Clin Invest 2011; 121: 671-682
    CrossrefPubMedGoogle Scholar
  • 19 Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature 2013; 496: 445-455
    CrossrefPubMedGoogle Scholar
  • 20 Dagvadorj J, Naiki Y, Tumurkhuu G, Hassan F, Islam S, Koide N, Mori I, Yoshida T, Yokochi T. Interleukin-10 inhibits tumor necrosis factor-alpha production in lipopolysaccharide-stimulated RAW 264.7 cells through reduced MyD88 expression. Innate Immun 2008; 14: 109-115
    CrossrefPubMedGoogle Scholar
  • 21 Medeiros AI, Serezani CH, Lee SP, Peters-Golden M. Efferocytosis impairs pulmonary macrophage and lung antibacterial function via PGE2/EP2 signaling. J Exp Med 2009; 206: 61-68
    CrossrefPubMedGoogle Scholar
  • 22 MacKenzie KF, Clark K, Naqvi S, McGuire VA, Nöehren G, Kristariyanto Y, van den Bosch M, Mudaliar M, McCarthy PC, Pattison MJ, Pedrioli PG, Barton GJ, Toth R, Prescott A, Arthur JS. PGE(2) induces macrophage IL-10 production and a regulatory-like phenotype via a protein kinase A-SIK-CRTC3 pathway. J Immunol 2013; 190: 565-577
    CrossrefPubMedGoogle Scholar
  • 23 Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, Gordon S, Hamilton JA, Ivashkiv LB, Lawrence T, Locati M, Mantovani A, Martinez FO, Mege JL, Mosser DM, Natoli G, Saeij JP, Schultze JL, Shirey KA, Sica A, Suttles J, Udalova I, van Ginderachter JA, Vogel SN, Wynn TA. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 2014; 41: 14-20
    CrossrefPubMedGoogle Scholar
  • 24 Grütz G. New insights into the molecular mechanism of interleukin-10-mediated immunosuppression. J Leukoc Biol 2005; 77: 3-15
    PubMedGoogle Scholar
  • 25 Driessler F, Venstrom K, Sabat R, Asadullah K, Schottelius AJ. Molecular mechanisms of interleukin-10-mediated inhibition of NF-kappaB activity: a role for p 50. Clin Exp Immunol 2004; 135: 64-73
    CrossrefPubMedGoogle Scholar
  • 26 Jin P, Chen Y, Lv L, Yang J, Lu H, Li L. Lactobacillus fermentum ZYL0401 attenuates lipopolysaccharide-induced hepatic TNF-α expression and liver injury via an IL-10- and PGE2-EP4-dependent mechanism. PLoS One 2015; 10: e0126520
    CrossrefPubMedGoogle Scholar
  • 27 Németh K, Leelahavanichkul A, Yuen PS, Mayer B, Parmelee A, Doi K, Robey PG, Leelahavanichkul K, Koller BH, Brown JM, Hu X, Jelinek I, Star RA, Mezey E. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med 2009; 15: 42-49
    CrossrefPubMedGoogle Scholar
  • 28 Zaslona Z, Serezani CH, Okunishi K, Aronoff DM, Peters-Golden M. Prostaglandin E2 restrains macrophage maturation via E prostanoid receptor 2/protein kinase A signaling. Blood 2012; 119: 2358-2367
    CrossrefPubMedGoogle Scholar
  • 29 Filgueiras LR, Koga MM, Quaresma PG, Ishizuka EK, Montes MB, Prada PO, Saad MJ, Jancar S, Rios FJ. PAFR in adipose tissue macrophages is associated with anti-inflammatory phenotype and metabolic homeostasis. Clin Sci (Lond) 2016; 130: 601-612
    CrossrefPubMedGoogle Scholar