European Journal of Nutrition

, Volume 56, Issue 3, pp 1077–1084 | Cite as

Effect of oleic acid on store-operated calcium entry in immune-competent cells

  • Celia CarrilloEmail author
  • María Giraldo
  • M. Mar Cavia
  • Sara R. Alonso-Torre
Original Contribution



To study the mechanism by which oleic acid (OA) (C18:1) exerts its beneficial effects on immune-competent cells. Since store-operated Ca2+ entry (SOCE) is a Ca2+ influx pathway involved in the control of multiple physiological processes including cell proliferation, we studied the effect of OA in Ca2+ signals of Jurkat T cells and THP-1 monocytes, paying particular attention to SOCE.


Changes in [Ca2+]i were measured using the Fura-2 fluorescence dye. Mn2+ uptake was monitored as a rate of quenching of Fura-2 fluorescence measured at the Ca2+-insensitive wavelengths. Thapsigargin was used to induce SOCE in Fura-2-loaded cells.


We showed a clear dose-dependent SOCE-inhibitory effect of OA in both cell lines. Such an inhibitory effect was PKC independent and totally restored by albumin, suggesting that OA exerts its effect somewhere in the membrane. We also demonstrated that OA induces increases in [Ca2+]i partly mediated by an extracellular Ca2+ influx through econazole-insensitive channels. Finally, we compared the effect of OA with stearic acid (C18:0), assuming the emerged evidence concerning the link between saturated fats and inflammation disorders. Stearic acid failed to inhibit SOCE, independently on the concentration tested, thus intensifying the physiological relevance of our findings.


We suggest a physiological pathway for the beneficial effects of OA in inflammation.


Oleic acid Ca2+ signals SOCE Immune-competent cells 



We thank Gonzalo Moreno for his technical support and M.L. Nieto for providing us the cells.


  1. 1.
    El-Gabalawy H, Guenther LC, Bernstein CN (2010) Epidemiology of immune-mediated inflammatory diseases: incidence, prevalence, natural history, and comorbidities. J Rheumatol Suppl 85:2–10CrossRefGoogle Scholar
  2. 2.
    Fogarty CL, Nieminen JK, Peräneva L et al (2015) High-fat meals induce systemic cytokine release without evidence of endotoxemia-mediated cytokine production from circulating monocytes or myeloid dendritic cells. Acta Diabetol 52:315–322CrossRefGoogle Scholar
  3. 3.
    Myles IA (2014) Fast food fever: reviewing the impacts of the Western diet on immunity. Nutr J 13:61CrossRefGoogle Scholar
  4. 4.
    Liu J, Hu S, Cui Y et al (2014) Saturated fatty acids up-regulate COX-2 expression in prostate epithelial cells via toll-like receptor 4/NF-κB signaling. Inflammation 37:467–477CrossRefGoogle Scholar
  5. 5.
    Anderson EK, Hill AA, Hasty AH (2012) Stearic acid accumulation in macrophages induces toll-like receptor 4/2-independent inflammation leading to endoplasmic reticulum stress-mediated apoptosis. Arterioscler Thromb Vasc Biol 32:1687–1695CrossRefGoogle Scholar
  6. 6.
    Frommer KW, Schäffler A, Rehart S et al (2015) Free fatty acids: potential proinflammatory mediators in rheumatic diseases. Ann Rheum Dis 74:303–310CrossRefGoogle Scholar
  7. 7.
    Wang S, Wu D, Matthan NR et al (2010) Reduction in dietary omega-6 polyunsaturated fatty acids: eicosapentaenoic acid plus docosahexaenoic acid ratio minimizes atherosclerotic lesion formation and inflammatory response in the LDL receptor null mouse. Atherosclerosis 204:147–155CrossRefGoogle Scholar
  8. 8.
    Galli C, Calder PC (2009) Effects of fat and fatty acid intake on inflammatory and immune responses: a critical review. Ann Nutr Metab 55:123–139CrossRefGoogle Scholar
  9. 9.
    Yates CM, Calder PC, Ed Rainger G (2014) Pharmacology and therapeutics of omega-3 polyunsaturated fatty acids in chronic inflammatory disease. Pharmacol Ther 141:272–282CrossRefGoogle Scholar
  10. 10.
    Calder PC (2015) Marine omega-3 fatty acids and inflammatory processes: effects, mechanisms and clinical relevance. Biochim Biophys Acta 1851:469–484CrossRefGoogle Scholar
  11. 11.
    García-Fernández E, Rico-Cabanas L, Rosgaard N et al (2014) Mediterranean diet and cardiodiabesity: a review. Nutrients 6:3474–3500CrossRefGoogle Scholar
  12. 12.
    Delgado-Lista J, Perez-Martinez P, Garcia-Rios A, et al. (2014) Mediterranean diet and cardiovascular risk: beyond traditional risk factors. Crit Rev Food Sci Nutr 37–41Google Scholar
  13. 13.
    Carrillo C, Cavia MM, Alonso-Torre S (2012) Role of oleic acid in immune system; mechanism of action; a review. Nutr Hosp 27:978–990Google Scholar
  14. 14.
    Sales-Campos H, Reis de Souza P, Crema Peghini B et al (2013) An overview of the modulatory effects of oleic acid in health and disease. Mini Rev Med Chem 13:201–210Google Scholar
  15. 15.
    Chemin J, Cazade M, Lory P (2014) Modulation of T-type calcium channels by bioactive lipids. Pflugers Arch 466:689–700CrossRefGoogle Scholar
  16. 16.
    Carrillo C, Cavia MM, Roelofs H et al (2011) Activation of human neutrophils by oleic acid involves the production of reactive oxygen species and a rise in cytosolic calcium concentration: a comparison with n-6 polyunsaturated fatty. Cell Physiol Biochem 28:329–338CrossRefGoogle Scholar
  17. 17.
    Carrillo C, Cavia MM, Alonso-Torre SR (2011) Oleic acid versus linoleic and α-linolenic acid. different effects on Ca2+ signaling in rat thymocytes. Cell Physioly Biochem 27:373–380CrossRefGoogle Scholar
  18. 18.
    Carrillo C, Hichami A, Andreoletti P et al (2012) Diacylglycerol-containing oleic acid induces increases in [Ca2+]i via TRPC3/6 channels in human T-cells. Biochim Biophys Acta 1821:618–626CrossRefGoogle Scholar
  19. 19.
    Berridge MJ (1995) Calcium signalling and cell proliferation. BioEssays 17:491–500CrossRefGoogle Scholar
  20. 20.
    Kahl CR, Means AR (2003) Regulation of cell cycle progression by calcium/calmodulin-dependent pathways. Endocr Rev 24:719–736CrossRefGoogle Scholar
  21. 21.
    Yang S-Y, Chang W-C (2013) The role of store-operated calcium channel in chronic inflammation. In: Chronic inflammation: causes, treatment options and role in disease, pp 1–18Google Scholar
  22. 22.
    Umemura M, Baljinnyam E, Feske S et al (2014) Store-operated Ca2+ entry (SOCE) regulates melanoma proliferation and cell migration. PLoS One 9:e89292CrossRefGoogle Scholar
  23. 23.
    Putney JW (1986) A model for receptor-regulated calcium entry. Cell Calcium 7:1–12CrossRefGoogle Scholar
  24. 24.
    Parekh A Jr, Putney J (2005) Store-operated calcium channels. Physiol Rev 85:757–810CrossRefGoogle Scholar
  25. 25.
    Alonso MT, Alvarez J, Montero M et al (1991) Agonist-induced Ca2+ influx into human platelets is secondary to the emptying of intracellular Ca2+ stores. Biochem J 280:783–789CrossRefGoogle Scholar
  26. 26.
    Montero M, Alvarez J, Garcia-Sancho J (1991) Agonist-induced Ca2+ influx in human neutrophils is secondary to the emptying of intracellular calcium stores. Biochem J 277:73–79CrossRefGoogle Scholar
  27. 27.
    Shaw PJ, Feske S (2012) Physiological and pathophysiological functions of SOCE in the immune system. Front Biosci (Elite Ed) 4:2253CrossRefGoogle Scholar
  28. 28.
    Núñez L, Valero RA, Senovilla L et al (2006) Cell proliferation depends on mitochondrial Ca2+ uptake: inhibition by salicylate. J Physiol 571:57–73CrossRefGoogle Scholar
  29. 29.
    Zitt C, Strauss B, Schwarz EC et al (2004) Potent inhibition of Ca2+ release-activated Ca2+ channels and T-lymphocyte activation by the pyrazole derivative BTP2. J Biol Chem 279:12427–12437CrossRefGoogle Scholar
  30. 30.
    Eiss HW, Mberger AA, Idschwendter MW et al (2001) Inhibition of store-operated calcium entry contributes to the anti-proliferative effect of non-steroidal anti-inflammatory. Int J Cancer 882:877–882Google Scholar
  31. 31.
    Carrillo C, Cavia MM, Alonso-Torre SR (2012) Oleic acid inhibits store-operated calcium entry in human colorectal adenocarcinoma cells. Eur J Nutr 51:677–684CrossRefGoogle Scholar
  32. 32.
    Grynkiewicz G, Poenie M, Tsien RY (1985) A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem 260:3440–3450Google Scholar
  33. 33.
    Thastrup O, Cullen PJ, Drøbak BK et al (1990) Thapsigargin, a tumor promoter, discharges intracellular Ca2+ stores by specific inhibition of the endoplasmic reticulum Ca2+-ATPase. Proc Natl Acad Sci 87:2466–2470CrossRefGoogle Scholar
  34. 34.
    Alonso MT, Sanchez A, Garcia-Sancho J (1989) Monitoring of the activation of receptor-operated calcium channels in human platelet. Biochem Biophys Res Commun 162:24–29CrossRefGoogle Scholar
  35. 35.
    Chen SG, Murakami K (1992) Synergistic activation of type III protein kinase C by cis-fatty acid and diacylglycerol. Biochem J 282:33–39CrossRefGoogle Scholar
  36. 36.
    Murakami K, Chan SY, Routtenberg A (1986) Protein kinase C activation by cis-fatty acid in the absence of Ca2+ and phospholipids. J Biol Chem 261:15424–15429Google Scholar
  37. 37.
    Meves H (2008) Arachidonic acid and ion channels: an update. Br J Pharmacol 155:4–16CrossRefGoogle Scholar
  38. 38.
    Chow C, Jondal M (1990) Ca2+ entry in T cells is activated by emptying the inositol 1,4,5-trisphosphate sensitive Ca2+ pool. Cell Calcium 11:641–646CrossRefGoogle Scholar
  39. 39.
    Carrillo C, Cavia MM, Alonso-Torre SR (2013) Effect of econazole on Ca2+ signaling in human colorectal adenocarcinoma cells. Turkish J Biochem 38:126–132CrossRefGoogle Scholar
  40. 40.
    Breittmayer JP, Pelassy C, Cousin JL et al (1993) The inhibition by fatty acids of receptor-mediated calcium movements in Jurkat T-cells is due to increased calcium extrusion. J Biol Chem 268:20812–20817Google Scholar
  41. 41.
    Khodorova A, Astashkin EI (1994) A dual effect of arachidonic acid on Ca2+ transport systems in lymphocytes. FEBS Lett 353:167–170CrossRefGoogle Scholar
  42. 42.
    Randriamampita C, Trautmann A (1990) Arachidonic acid activates Ca2+ extrusion in macrophages. J Biol Chem 265:16059–16062Google Scholar
  43. 43.
    Chow SC, Ansotegui IJ, Jondal M (1990) Inhibition of receptor-mediated calcium influx in T cells by unsaturated non-esterified fatty acids. Biochem J 267:727–732CrossRefGoogle Scholar
  44. 44.
    Ekokoski E, Forss L, Tormquist K (1994) Inhibitory action of fatty acids on calcium fluxes in thyroid FRTL-5 cells. Mol Cell Endocrinol 103:125–132CrossRefGoogle Scholar
  45. 45.
    Alonso-Torre SR, Garcı́a-Sancho J (1997) Arachidonic acid inhibits capacitative calcium entry in rat thymocytes and human neutrophils. Biochim Biophys Acta Biomembranes 1328:207–213CrossRefGoogle Scholar
  46. 46.
    Gamberucci A, Fulceri R, Benedetti A (1997) Inhibition of store-dependent capacitative Ca2+ influx by unsaturated fatty acids. Cell Calcium 21:375–385CrossRefGoogle Scholar
  47. 47.
    Gamberucci A, Fulceri R, Bygrave FL, Benedetti A (1997) Unsaturated fatty acids mobilize intracellular calcium independent of IP3 generation and VIA insertion at the plasma membrane. Biochem Biophys Res Commun 241:312–316CrossRefGoogle Scholar
  48. 48.
    Bonin A, Khan NA (2000) Regulation of calcium signalling by docosahexaenoic acid in human T-cells: implication of CRAC channels. J Lipid Res 41:277–284Google Scholar
  49. 49.
    Villalobos C, García-Sancho J (1995) Capacitative Ca2+ entry contributes to the Ca2+ influx induced by thyrotropin-releasing hormone (TRH) in GH3 pituitary cells. Pflugers Arch 430:923–935CrossRefGoogle Scholar
  50. 50.
    Aires V, Hichami A, Filomenko R et al (2007) Docosahexaenoic acid induces increases in [Ca2+]i via inositol 1,4,5-triphosphate production and activates protein kinase C gamma and -delta via phosphatidylserine binding site: implication in apoptosis in U937 cells. Mol Pharmacol 72:1545–1556CrossRefGoogle Scholar
  51. 51.
    Mena J, Manosalva C, Ramirez R et al (2013) Linoleic acid increases adhesion, chemotaxis, granule release, intracellular calcium mobilisation, MAPK phosphorylation and gene expression in bovine neutrophils. Vet Immunol Immunopathol 151:275–284CrossRefGoogle Scholar
  52. 52.
    Thompson MA, Prakash YS, Pabelick CM (2014) Arachidonate-regulated Ca2+ influx in human airway smooth muscle. Am J Respir Cell Mol Biol 51:68–76CrossRefGoogle Scholar
  53. 53.
    Hidalgo MA, Nahuelpan C, Manosalva C et al (2011) Oleic acid induces intracellular calcium mobilization, MAPK phosphorylation, superoxide production and granule release in bovine neutrophils. Biochem Biophys Res Commun 409:280–286CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Celia Carrillo
    • 1
    Email author
  • María Giraldo
    • 1
  • M. Mar Cavia
    • 1
  • Sara R. Alonso-Torre
    • 1
  1. 1.Nutrition and Food Science, Faculty of SciencesUniversity of BurgosBurgosSpain

Personalised recommendations