Advertisement

Inflammation

pp 1–14 | Cite as

Investigation of Modulatory Effect of Pinolenic Acid (PNA) on Inflammatory Responses in Human THP-1 Macrophage-Like Cell and Mouse Models

  • Szu-Jung Chen
  • Wen-Cheng Huang
  • Hung-Jing Shen
  • Ruei-Yu Chen
  • Hsiang Chang
  • Yun-Shan Ho
  • Po-Jung TsaiEmail author
  • Lu-Te ChuangEmail author
Original Article
  • 15 Downloads

Abstract

Pinolenic acid (PNA) is a rare n-6 polyunsaturated fatty acid (n-6 PUFA) originally identified in pine seeds. Previous studies demonstrated that PNA and its elongation metabolite, Δ7-eicosatrienoic acid (Δ7-ETrA), exerted an anti-inflammatory effect in cultured cells by suppressing prostaglandin E2 (PGE2) production. The objective of this study was to further examine the in vivo anti-inflammatory properties of PNA. Using human THP-1 macrophage, we first confirmed that incorporation of PNA into cellular phospholipids suppressed the production of interleukin-6 (IL-6) (by 46%), tumor necrosis factor-α (TNF-α) (by 18%), and prostaglandin E2 (PGE2) (by 87%), and the expression of type-2 cyclooxygenase (COX-2) (by 27%). Furthermore, we demonstrated that injection of PNA or Δ7-ETrA suppressed 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse ear edema, as measured by ear thickness (by 15%) and biopsy weight (by up to 29%). Both PUFA also lowered proportions of infiltrated leukocytes, neutrophils, and macrophages using flow cytometric analysis. Topical application of PNA or Δ7-ETrA on mouse back skin suppressed TPA-induced pro-inflammatory mediator production, including IL-1β, IL-6, TNF-α, and PGE2, as well as the phosphorylation of p38- and JNK-mitogen-activated protein kinase (MAPK), but not that of ERK-MAPK. That no PNA or Δ7-ETrA was detected in the ear disc after the PUFA injection suggests that their anti-inflammatory effect might not be due to fatty acid incorporation, but to modulation of cell signaling. In conclusion, PNA and Δ7-ETrA exerted the in vivo anti-inflammatory effect by suppressing mouse ear edema and dorsal skin inflammation.

KEY WORDS

pinolenic acid (PNA) Δ7-eicosatrienoic acid (Δ7-ETrA) polyunsaturated fatty acids (PUFA) inflammation mouse ear edema 

Notes

Acknowledgments

The authors are grateful to Professor Robert H. Glew, PhD, for editing our manuscript.

Funding Information

This work was supported in part by research grants from the Ministry of Science and Technology, Executive Yuan, Taiwan (MOST 104-2320-B-264-002- and MOST 105-2320-B-264-001) and the Tao Yuan General Hospital, Ministry of Health and Welfare, The Executive Yuan, Taiwan (PTH10408), respectively.

Compliance with Ethical Standards

All procedures were approved by the Institutional Animal Care and Use Committee of Yuanpei University of Medical Technology (IACUC Approval No. LAC10301).

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Sugano, M., I. Ikeda, K. Wakamatsu, and Y. Oka. 1994. Influence of Korean pine (Pinus koraiensis)-seed oil containing cis-5, cis-9, cis-12-octadecatrienoic acid on polyunsaturated fatty acid metabolism, eicosanoid production and blood pressure. British Journal of Nutrition 72: 775–783.CrossRefGoogle Scholar
  2. 2.
    Wolff, R.L., O. Lavialle, F. Pédrono, E. Pasquier, L.G. Deluc, A.M. Marpeau, and K. Aitzetmüller. 2001. Fatty acid composition of Pinaceae as taxonomic markers. Lipids 36: 439–451.CrossRefGoogle Scholar
  3. 3.
    Wolff, R.L., W.W. Christie, F. Pédrono, and A.M. Marpeau. 1999. Arachidonic, eicosapentaenoic, and biosynthetically related fatty acids in the seed lipids from a primitive gymnosperm, Agathis robusta. Lipids 34: 1083–1097.CrossRefGoogle Scholar
  4. 4.
    Leonard, A.E., B. Kelder, E.G. Bobik, L.-T. Chuang, J.M. Parker-Barnes, J.M. Thurmond, P.E. Kroeger, J.J. Kopchick, Y.-S. Huang, and P. Mukerji. 2000. cDNA cloning and characterization of human ∆5-desaturase involved in the biosynthesis of arachidonic acid. Biochemical Journal 347: 719–724.CrossRefGoogle Scholar
  5. 5.
    Innes, J.K., and P.C. Calder. 2018. Omega-6 fatty acids and inflammation. Prostaglandins, Leukotrienes and Essential Fatty Acids 132: 41–48.CrossRefGoogle Scholar
  6. 6.
    Tanaka, T., T. Takimoto, J.-I. Morishige, Y. Kikuta, T. Sugiura, and K. Satouchi. 1999. Non-methylene-interrupted polyunsaturated fatty acids: Effective substitutes for arachidonate of phosphatidylinositol. Biochemical and Biophysical Research Communication 264: 683–688.CrossRefGoogle Scholar
  7. 7.
    Chuang, L.-T., P.-J. Tsai, C.-L. Lee, and Y.-S. Huang. 2009. Uptake and incorporation of pinolenic acid reduces n-6 polyunsaturated fatty acid and downstream prostaglandin formation in murine macrophage. Lipids 44: 217–224.CrossRefGoogle Scholar
  8. 8.
    Huang, W.-C., P.-J. Tsai, Y.-L. Huang, S.-N. Chen, and L.-T. Chuang. 2014. PGE2 production suppressed by chemically-synthesized Δ7-eicosatrienoic acid in macrophages through the competitive inhibition of COX-2. Food and Chemical Toxicology 66: 122–133.CrossRefGoogle Scholar
  9. 9.
    Chen, S.-J., C.-P. Hsu, C.-W. Li, J.-H. Lu, and L.-T. Chuang. 2011. Pinolenic acid inhibits human breast cancer MDA-MB-231 cell metastasis in vitro. Food Chemistry 126: 1708–1715.CrossRefGoogle Scholar
  10. 10.
    Chen, S.-J., L.-T. Chuang, J.-S. Liao, W.-C. Huang, and H.-H. Lin. 2015. Phospholipid incorporation of non-methylene-interrupted fatty acids (NMIFA) in murine microglial BV-2 cells reduces pro-inflammatory mediator production. Inflammation 38: 2133–2145.CrossRefGoogle Scholar
  11. 11.
    Tanaka, T., T. Hattori, M. Kouchi, K. Hirano, and K. Satouchi. 1998. Non-methylene-interrupted polyenoic fatty acids: Structural characterization and metabolism by fatty acid chain elongation system in rat liver. In Essential fatty acids and eicosanoids, ed. R.A. Tiemersma, R. Armstrong, R.W. Kelly, and R. Wilson, 229–233. Champaign: American Oil Chemists’ Society Press.Google Scholar
  12. 12.
    Pasquier, E., W.M. Ratnayake, and R.L. Wolff. 2001. Effects of delta5 polyunsaturated fatty acids of maritime pine (Pinus pinaster) seed oil on the fatty acid profile of the developing brain of rats. Lipids 36: 567–574.CrossRefGoogle Scholar
  13. 13.
    Folch, J., M. Lees, and G.H. Sloane-Stanley. 1957. A simple method for the isolation and purification of total lipids from animal tissues. Journal of Biological Chemistry 226: 497–509.Google Scholar
  14. 14.
    Robertson, F.M., M.S. Ross, K.L. Tober, B.W. Long, and T.M. Oberyszyn. 1996. Inhibition of pro-inflammatory cytokine gene expression and papilloma growth during murine multistage carcinogenesis by pentoxifylline. Carcinogenesis 17: 1719–1728.CrossRefGoogle Scholar
  15. 15.
    Huang, W.-C., T.-H. Tsai, C.-J. Huang, Y.-Y. Li, J.-H. Chyuan, L.-T. Chuang, and P.-J. Tsai. 2015. Inhibitory effects of wild bitter melon leaf extract on Propionibacterium acnes-induced skin inflammation in mice and cytokine production in vitro. Food and Function 6: 2550–2560.CrossRefGoogle Scholar
  16. 16.
    Tsai, P.-J., W.-C. Huang, M.-C. Hsieh, P.-J. Sung, Y.-H. Kuo, and W.-H. Wu. 2016. Flavones isolated from Scutellariae radix suppress Propionibacterium acnes-induced cytokine production in vitro and in vivo. Molecules 21: 15.CrossRefGoogle Scholar
  17. 17.
    Das, U.N., M.E. Begin, and G. Ells. 1992. Fatty acid changes during the induction of differentiation of human promyelocytic leukemia (HL-60) cells by phorbolmyristate acetate. Prostaglandins, Leukotrienes and Essential Fatty Acids 146: 235–239.CrossRefGoogle Scholar
  18. 18.
    Horrobin, D.F. 1993. Fatty acid metabolism in health and disease: The role of delta-6-desaturase. American Journal of Clinical Nutrition 57: 732S–736S.CrossRefGoogle Scholar
  19. 19.
    Wong, S.W., M.J. Kwon, A.M. Choi, H.P. Kim, K. Nakahira, and D.H. Hwang. 2009. Fatty acids modulate Toll-like receptor 4 activation through regulation of receptor dimerization and recruitment into lipid rafts in a reactive oxygen species-dependent manner. Journal of Biological Chemistry 284: 27384–27392.CrossRefGoogle Scholar
  20. 20.
    Kim, W., N.A. Khan, D.N. McMurray, I.A. Prior, N. Wang, and R.S. Chapkin. 2010. Regulatory activity of polyunsaturated fatty acids in T-cell signaling. Progress in Lipid Research 49: 250–261.CrossRefGoogle Scholar
  21. 21.
    Tsai, P.-J., W.-C. Huang, S.-W. Lin, S.-N. Chen, H.-J. Shen, H. Chang, and L.-T. Chuang. 2018. Juniperonic acid incorporation into the phospholipids of murine macrophage cells modulates pro-inflammatory mediator production. Inflammation 41: 1200–1214.CrossRefGoogle Scholar
  22. 22.
    Monmai, C., S.H. Go, I.S. Shin, S.G. You, H. Lee, S.B. Kang, and W.J. Park. 2018. Immune-enhancement and anti-inflammatory activities of fatty acids extracted from Halocynthia aurantium tunic in RAW264.7 cells. Marine Drugs 16: E309.CrossRefGoogle Scholar
  23. 23.
    McDaniel, J.C., K. Massey, and A. Nicolaou. 2011. Fish oil supplementation alters levels of lipid mediators of inflammation in microenvironment of acute human wounds. Wound Repair and Regeneration 19: 189–200.CrossRefGoogle Scholar
  24. 24.
    Raederstorff, D., M. Pantze, H. Bachmann, and U. Moser. 1996. Anti-inflammatory properties of docosahexaenoic and eicosapentaenoic acids in phorbol-ester-induced mouse ear inflammation. International Archives of Allergy and Immunology 111: 284–290.CrossRefGoogle Scholar
  25. 25.
    Hwang, J.K., H.N. Yu, E.M. Noh, J.M. Kim, O.Y. Hong, H.J. Youn, S.H. Jung, K.B. Kwon, J.S. Kim, and Y.R. Lee. 2017. DHA blocks TPA-induced cell invasion by inhibiting MMP-9 expression via suppression of the PPAR-γ/NF-κB pathway in MCF-7 cells. Oncology Letters 13: 243–249.CrossRefGoogle Scholar
  26. 26.
    Ibrahim, A., K. Mbodji, A. Hassan, M. Aziz, N. Boukhettala, M. Coëffier, G. Savoye, P. Déchelottec, and R. Marion-Letelliera. 2011. Anti-inflammatory and antiangiogenic effect of long-chain n-3 polyunsaturated fatty acids in intestinal microvascular endothelium. Clinical Nutrition 30: 678–687.CrossRefGoogle Scholar
  27. 27.
    Ziboh, V.A. 1996. The biological/nutritional significance of γ-linolenic acid in the epidermis: metabolism and generation of potent biological modulators. In γ-Linolenic acid: Metabolism and its roles in nutrition and medicine, ed. Y.-S. Huang and D.E. Mills, 118–128. Champaign: American Oil Chemists’ Society Press.Google Scholar
  28. 28.
    Simon, D., P.A. Eng, S. Borelli, R. Kägi, C. Zimmermann, C. Zahner, J. Drewe, L. Hess, G. Ferrari, S. Lautenschlager, B. Wüthrich, and P. Schmid-Grendelmeier. 2014. Gamma-linolenic acid levels correlate with clinical efficacy of evening primrose oil in patients with atopic dermatitis. Advances in Therapy 31: 180–188.CrossRefGoogle Scholar
  29. 29.
    Fan, F.-Y., and R.S. Chapkin. 1998. Importance of dietary γ-linolenic acid in human health and nutrition. Journal of Nutrition 128: 1411–1414.CrossRefGoogle Scholar
  30. 30.
    Ziboh, V.A., S. Naguwa, K. Vang, J. Wineinger, B.M. Morrissey, M. Watnik, and M.E. Gershwin. 2004. Suppression of leukotriene B4 generation by ex-vivo neutrophils isolated from asthma patients on dietary supplementation with gammalinolenic acid-containing borage oil: possible implication in asthma. Clinical and Developmental Immunology 11: 13–21.CrossRefGoogle Scholar
  31. 31.
    Sergeant, S., E. Rahbar, and F.H. Chilton. 2016. Gamma-linolenic acid, dihommo-gamma linolenic, eicosanoids and inflammatory processes. European Journal of Pharmacology 785: 77–86.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Radiation OncologyTao Yuan General HospitalTaoYuanTaiwan
  2. 2.Department of Human Development and Family StudiesNational Taiwan Normal UniversityTaipeiTaiwan
  3. 3.Department of Biotechnology and Pharmaceutical TechnologyYuanpei University of Medical TechnologyHsinchuTaiwan
  4. 4.Program of Nutritional Science, School of Life ScienceNational Taiwan Normal UniversityTaipeiTaiwan

Personalised recommendations