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

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
• 2 Guimarães AG, Quintans JS, Quintans jr. LJ. Monoterpenes with analgesic activity – a systematic review. Phytother Res 2013; 27: 1-15
• 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
• 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
• 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
• 6 Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol 2005; 5: 953-964
• 7 Fleming BD, Mosser DM. Regulatory macrophages: setting the threshold for therapy. Eur J Immunol 2011; 41: 2498-2502
• 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
• 9 Saraiva M, OʼGarra A. The regulation of IL-10 production by immune cells. Nat Rev Immunol 2010; 10: 170-181
• 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
• 11 Kühn R, Löhler J, Rennick D, Rajewsky K, Müller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 1993; 75: 263-274
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 19 Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature 2013; 496: 445-455
• 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
• 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
• 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
• 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
• 24 Grütz G. New insights into the molecular mechanism of interleukin-10-mediated immunosuppression. J Leukoc Biol 2005; 77: 3-15
• 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
• 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
• 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
• 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
• 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