Herbal extracts that induce type I interferons through Toll-like receptor 4 signaling

  • Misa Nakasuji-Togi Division of Developmental Biology, Eunice Kennedy Institute of Child Health and Human Development, National Institutes of Health, MD, USA; Department of Regenerative Medicine, School of Medicine, Kanazawa Medical University, Ishikawa, Japan; Center for Regenerative Medicine, Kanazawa Medical University Hospital, Ishikawa, Japan https://orcid.org/0000-0002-7424-4548
  • Sumihito Togi Division of Developmental Biology, Eunice Kennedy Institute of Child Health and Human Development, National Institutes of Health, MD, USA; Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Ishikawa, Japan; Center for Clinical Genomics, Kanazawa Medical University Hospital, Ishikawa, Japan https://orcid.org/0000-0002-3189-8111
  • Keita Saeki Division of Developmental Biology, Eunice Kennedy Institute of Child Health and Human Development, National Institutes of Health, MD, USA https://orcid.org/0000-0002-0611-176X
  • Yasuhiko Kojima NPO Interferon Herb Research Institute, Tokyo, Japan
  • Keiko Ozato Division of Developmental Biology, Eunice Kennedy Institute of Child Health and Human Development, National Institutes of Health, MD, USA
Keywords: herbal medicine; interferon; pathogen resistance; macrophages; toll-like receptors

Abstract

Background: A mixture of five herbal extracts called internatural (INT), which is prepared from pumpkin seeds, purple turmeric, pearl barley, corn pistil, and cinnamon, is widely used by people in Japan and elsewhere for its immunity-enhancing effects and general health. Although anecdotal evidence indicates its efficacy, the mechanisms by which INT boosts immunity have remained unknown.

Objective: The aim of this study was to investigate whether INT induces type I interferons (IFNs) in murine bone marrow-derived macrophages (BMDMs) and by what mechanism.

Design: We measured induction of type I IFNs (IFNβ and IFNα) in BMDMs treated with INT or other Toll-like receptor ligands: bacterial lipopolysaccharides (LPS), dsRNA, poly(I:C), and CpG oligonucleotides. To investigate whether INT signals through Toll-like receptor 4 (TLR4), we tested TLR4-specific inhibitor. We also tested if INT utilizes TLR4 adaptors, toll/IL-1 receptor (TIR) domain-containing adaptor (TRIF), or myeloid differentiation factor 88 (MyD88), we examined INT induction of IFNβ in TRIF-KO and MyD88-KO BMDMs. We then investigated whether INT provides an antiviral effect upon fibroblasts either directly or indirectly using the encephalomyocarditis virus (EMCV) model.

Results: We first observed that INT, when added to BMDMs, potently induces type I IFNs (IFNβ and IFNα) within 2 h. INT induction of IFN expression was mediated by TLR4, which signaled through the TRIF/MyD88 adaptors, similar to LPS. A high-molecular-weight fraction (MW > 10,000) of INT extracts contained IFN-inducing activity. Supernatants from INT-treated BMDMs protected untreated fibroblast from EMCV infection as reduced viral titers.

Conclusions: INT induced type I IFN mRNA and proteins in BMDMs and other cell types. This induction was mediated by TLR4, which transduces signals using the TRIF/MyD88 pathway. The high-MW component of INT contained type I IFN inducing activity. The supernatants from INT-treated cells displayed antiviral activity and protected cells from EMCV infection. These findings indicate that INT is a novel natural IFN inducer that strengthens host’s innate immunity.

Downloads

Download data is not yet available.

Author Biographies

Misa Nakasuji-Togi, Division of Developmental Biology, Eunice Kennedy Institute of Child Health and Human Development, National Institutes of Health, MD, USA; Department of Regenerative Medicine, School of Medicine, Kanazawa Medical University, Ishikawa, Japan; Center for Regenerative Medicine, Kanazawa Medical University Hospital, Ishikawa, Japan
  • Department of Regenerative Medicine, School of Medicine
  • Research Assistant
Sumihito Togi, Division of Developmental Biology, Eunice Kennedy Institute of Child Health and Human Development, National Institutes of Health, MD, USA; Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Ishikawa, Japan; Center for Clinical Genomics, Kanazawa Medical University Hospital, Ishikawa, Japan
  • Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute
  • Assistant Professor
Keita Saeki, Division of Developmental Biology, Eunice Kennedy Institute of Child Health and Human Development, National Institutes of Health, MD, USA
  • Division of Developmental Biology, Eunice Kennedy Institute of Child Health and Human Development
  •  Visiting Fellow
Keiko Ozato, Division of Developmental Biology, Eunice Kennedy Institute of Child Health and Human Development, National Institutes of Health, MD, USA
  • Division of Developmental Biology, Eunice Kennedy Institute of Child Health and Human Development

  • Principal Investigator

References


  1. Kaur S, Uddin S, Platanias LC. The PI3’ kinase pathway in interferon signaling. J Interferon Cytokine Res 2005; 25: 780–7. doi: 10.1089/jir.2005.25.780

  2. MacMicking JD. Interferon-inducible effector mechanisms in cell-autonomous immunity. Nat Rev Immunol 2012; 12: 367–82. doi: 10.1038/nri3210

  3. Chen J, Baig E, Fish EN. Diversity and relatedness among the type I interferons. J Interferon Cytokine Res 2004; 24: 687–98. doi: 10.1089/jir.2004.24.687

  4. van Pesch V, Lanaya H, Renauld JC, Michiels T. Characterization of the murine alpha interferon gene family. J Virol 2004; 78: 8219–28. doi: 10.1128/jvi.78.15.8219-8228.2004

  5. Kawai T, Akira S. Toll-like receptor and RIG-I-like receptor signaling. Ann N Y Acad Sci 2008; 1143: 1–20. doi: 10.1196/annals.1443.020

  6. O’Neill LA, Bowie AG. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol 2007; 7: 353–64. doi: 10.1038/nri2079

  7. O’Neill LA, Golenbock D, Bowie AG. The history of Toll-like receptors – redefining innate immunity. Nat Rev Immunol 2013; 13: 453–60. doi: 10.1038/nri3446

  8. Adachi O, Kawai T, Takeda K, Matsumoto M, Tsutsui H, Sakagami M, et al. Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity 1998; 9: 143–50. doi: 10.1016/s1074-7613(00)80596-8

  9. Marié I, Durbin JE, Levy DE. Differential viral induction of distinct interferon-alpha genes by positive feedback through interferon regulatory factor-7. Embo J 1998; 17: 6660–9. doi: 10.1093/emboj/17.22.6660

  10. Tailor P, Tamura T, Kong HJ, Kubota T, Kubota M, Borghi P, et al. The feedback phase of type I interferon induction in dendritic cells requires interferon regulatory factor 8. Immunity 2007; 27: 228–39. doi: 10.1016/j.immuni.2007.06.009

  11. Corrales L, Glickman LH, McWhirter SM, Kanne DB, Sivick KE, Katibah GE, et al. Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity. Cell Rep 2015; 11: 1018–30. doi: 10.1016/j.celrep.2015.04.031

  12. Doherty MR, Cheon H, Junk DJ, Vinayak S, Varadan V, Telli ML, et al. Interferon-beta represses cancer stem cell properties in triple-negative breast cancer. Proc Natl Acad Sci USA 2017; 114: 13792–7. doi: 10.1073/pnas.1713728114

  13. Ji HF, Li XJ, Zhang HY. Natural products and drug discovery. Can thousands of years of ancient medical knowledge lead us to new and powerful drug combinations in the fight against cancer and dementia? EMBO Rep 2009; 10: 194–200. doi: 10.1038/embor.2009.12

  14. Petrovska BB. Historical review of medicinal plants’ usage. Pharmacogn Rev 2012; 6: 1–5. doi: 10.4103/0973-7847.95849

  15. Lin CW, Wu CF, Hsiao NW, Chang CY, Li SW, Wan L, et al. Aloe-emodin is an interferon-inducing agent with antiviral activity against Japanese encephalitis virus and enterovirus 71. Int J Antimicrob Agents 2008; 32: 355–9. doi: 10.1016/j.ijantimicag.2008.04.018

  16. Yue Y, Li Z, Li P, Song N, Li B, Lin W, et al. Antiviral activity of a polysaccharide from Laminaria japonica against enterovirus 71. Biomed Pharmacother 2017; 96: 256–62. doi: 10.1016/j.biopha.2017.09.117

  17. Lin LT, Hsu WC, Lin CC. Antiviral natural products and herbal medicines. J Tradit Complement Med 2014; 4: 24–35. doi: 10.4103/2225-4110.124335

  18. Huang XY, Huang ZL, Wang L, Xu YH, Huang XY, Ai KX, et al. Herbal compound ‘Songyou Yin’ reinforced the ability of interferon-alfa to inhibit the enhanced metastatic potential induced by palliative resection of hepatocellular carcinoma in nude mice. BMC Cancer 2010; 10: 580. doi: 10.1186/1471-2407-10-580

  19. Han C, Kawata M, Hamada Y, Kondo T, Wada J, Asano K, et al. Analyses of the possible anti-tumor effect of yokukansan. J Nat Med 2019; 73: 468–79. doi: 10.1007/s11418-019-01283-x

  20. Kojima Y, Hashimoto H, Shibukawa N. Priming effect of interferon on the production of endotoxin-induced interferon in rabbits and rabbit lymphoid cells. Ann N Y Acad Sci 1980; 350: 632. doi: 10.1111/j.1749-6632.1980.tb20693.x

  21. Hashimoto H, Shibukawa N, Kojima Y. The mode of production of endotoxin-induced interferon in rabbit lymphoid cell cultures. II. Priming effect of interferon on apparently noninducible cells. Microbiol Immunol 1979; 23: 1033–6. doi: 10.1111/j.1348-0421.1979.tb00533.x

  22. Ozato K, Uno K, Iwakura Y. Another road to interferon: Yasuichi Nagano’s journey. J Interferon Cytokine Res 2007; 27: 349–52. doi: 10.1089/jir.2007.9988

  23. Ayithan N, Bradfute SB, Anthony SM, Stuthman KS, Dye JM, Bavari S, et al. Ebola virus-like particles stimulate type I interferons and proinflammatory cytokine expression through the toll-like receptor and interferon signaling pathways. J Interferon Cytokine Res 2014; 34: 79–89. doi: 10.1089/jir.2013.0035

  24. Ivashkiv LB, Donlin LT. Regulation of type I interferon responses. Nat Rev Immunol 2014; 14: 36–49. doi: 10.1038/nri3581

  25. Tsujimura H, Tamura T, Ozato K. Cutting edge: IFN consensus sequence binding protein/IFN regulatory factor 8 drives the development of type I IFN-producing plasmacytoid dendritic cells. J Immunol 2003; 170: 1131–5. doi: 10.4049/jimmunol.170.3.1131

  26. Kamada R, Yang W, Zhang Y, Patel MC, Yang Y, Ouda R, et al. Interferon stimulation creates chromatin marks and establishes transcriptional memory. Proc Natl Acad Sci USA 2018; 115: E9162–71. doi: 10.1073/pnas.1720930115

  27. Yamamoto M, Sato S, Hemmi H, Uematsu S, Hoshino K, Kaisho T, et al. TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat Immunol 2003; 4: 1144–50. doi: 10.1038/ni986

  28. Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, Sanjo H, et al. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 2003; 301: 640–3. doi: 10.1126/science.1087262

  29. Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell 2010; 140: 805–20. doi: 10.1016/j.cell.2010.01.022

  30. Pålsson-McDermott EM, O’Neill LA. Signal transduction by the lipopolysaccharide receptor, Toll-like receptor-4. Immunology 2004; 113: 153–62. doi: 10.1111/j.1365-2567.2004.01976.x

  31. Ii M, Matsunaga N, Hazeki K, Nakamura K, Takashima K, Seya T, et al. A novel cyclohexene derivative, ethyl (6R)-6-[N-(2-Chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242), selectively inhibits toll-like receptor 4-mediated cytokine production through suppression of intracellular signaling. Mol Pharmacol 2006; 69: 1288–95. doi: 10.1124/mol.105.019695

  32. Kawamoto T, Ii M, Kitazaki T, Iizawa Y, Kimura H. TAK-242 selectively suppresses Toll-like receptor 4-signaling mediated by the intracellular domain. Eur J Pharmacol 2008; 584: 40–8. doi: 10.1016/j.ejphar.2008.01.026

  33. Domingues MM, Inácio RG, Raimundo JM, Martins M, Castanho MA, Santos NC. Biophysical characterization of polymyxin B interaction with LPS aggregates and membrane model systems. Biopolymers 2012; 98: 338–44. doi: 10.1002/bip.22095

  34. Cardoso LS, Araujo MI, Góes AM, Pacífico LG, Oliveira RR, Oliveira SC. Polymyxin B as inhibitor of LPS contamination of Schistosoma mansoni recombinant proteins in human cytokine analysis. Microb Cell Fact 2007; 6: 1. doi: 10.1186/1475-2859-6-1

  35. Liu YJ. IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu Rev Immunol 2005; 23: 275–306. doi: 10.1146/annurev.immunol.23.021704.115633

  36. Dalod M, Salazar-Mather TP, Malmgaard L, Lewis C, Asselin-Paturel C, Brière F, et al. Interferon alpha/beta and interleukin 12 responses to viral infections: pathways regulating dendritic cell cytokine expression in vivo. J Exp Med 2002; 195: 517–28. doi: 10.1084/jem.20011672

  37. Yoshimi R, Chang TH, Wang H, Atsumi T, Morse HC, 3rd, Ozato K. Gene disruption study reveals a nonredundant role for TRIM21/Ro52 in NF-kappaB-dependent cytokine expression in fibroblasts. J Immunol 2009; 182: 7527–38. doi: 10.4049/jimmunol.0804121

  38. Brawand P, Fitzpatrick DR, Greenfield BW, Brasel K, Maliszewski CR, De Smedt T. Murine plasmacytoid pre-dendritic cells generated from Flt3 ligand-supplemented bone marrow cultures are immature APCs. J Immunol 2002; 169: 6711–9. doi: 10.4049/jimmunol.169.12.6711

  39. Carocci M, Bakkali-Kassimi L. The encephalomyocarditis virus. Virulence 2012; 3: 351–67. doi: 10.4161/viru.20573

  40. Crow MK. Type I interferon in organ-targeted autoimmune and inflammatory diseases. Arthritis Res Ther 2010; 12 Suppl 1(Suppl 1): S5. doi: 10.1186/ar2886

  41. Munford RS. Sensing gram-negative bacterial lipopolysaccharides: a human disease determinant? Infect Immun 2008; 76: 454–65. doi: 10.1128/iai.00939-07

  42. Biswas SK, Lopez-Collazo E. Endotoxin tolerance: new mechanisms, molecules and clinical significance. Trends Immunol 2009; 30: 475–87. doi: 10.1016/j.it.2009.07.009

  43. Peri F, Calabrese V. Toll-like receptor 4 (TLR4) modulation by synthetic and natural compounds: an update. J Med Chem 2014; 57: 3612–22. doi: 10.1021/jm401006s

  44. Lancaster GI, Langley KG, Berglund NA, Kammoun HL, Reibe S, Estevez E, et al. Evidence that TLR4 is not a receptor for saturated fatty acids but mediates lipid-induced inflammation by reprogramming macrophage metabolism. Cell Metab 2018; 27: 1096–110.e5. doi: 10.1016/j.cmet.2018.03.014

  45. Wang Y, Su L, Morin MD, Jones BT, Whitby LR, Surakattula MM, et al. TLR4/MD-2 activation by a synthetic agonist with no similarity to LPS. Proc Natl Acad Sci USA 2016; 113: E884–93. doi: 10.1073/pnas.1525639113

Published
2022-01-28
How to Cite
Nakasuji-TogiM., TogiS., SaekiK., KojimaY., & OzatoK. (2022). Herbal extracts that induce type I interferons through Toll-like receptor 4 signaling. Food & Nutrition Research, 66. https://doi.org/10.29219/fnr.v66.5524
Section
Original Articles