Toll-Like Receptor-Dependent Immunomodulatory Activity of Pycnogenol®

Annelies Verlaet, Nieke van der Bolt, Ben Meijer, Annelies Breynaert, Tania Naessens, Prokopis Konstanti, Hauke Smidt, Nina Hermans, Huub F.J. Savelkoul, Malgorzata Teodorowicz

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

BACKGROUND: Pycnogenol® (PYC), an extract of French maritime pine bark, is widely used as a dietary supplement. PYC has been shown to exert anti-inflammatory actions via inhibiting the Toll-like receptor 4 (TLR4) pathway. However, the role of the other receptors from the TLR family in the immunomodulatory activity of PYC has not been described so far. AIM: The aim of this study was to investigate whether PYC might exert its immunomodulatory properties through cell membrane TLRs (TLR1/2, TLR5, and TLR2/6) other than TLR4. Moreover, the effect of gastrointestinal metabolism on the immunomodulatory effects of PYC was investigated. FINDINGS: We showed that intact non-metabolized PYC dose-dependently acts as an agonist of TLR1/2 and TLR2/6 and as a partial agonist of TLR5. PYC on its own does not agonize or antagonize TLR4. However, after the formation of complexes with lipopolysaccharides (LPS), it is a potent activator of TLR4 signaling. Gastrointestinal metabolism of PYC revealed the immunosuppressive potential of the retentate fraction against TLR1/2 and TLR2/6 when compared to the control fraction containing microbiota and enzymes only. The dialyzed fraction containing PYC metabolites revealed the capacity to induce anti-inflammatory IL-10 secretion. Finally, microbially metabolized PYC affected the colonic microbiota composition during in vitro gastrointestinal digestion. CONCLUSIONS: This study showed that gastrointestinal metabolism of PYC reveals its biological activity as a potential inhibitor of TLRs signaling. The results suggest that metabolized PYC acts as a partial agonist of TLR1/2 and TLR2/6 in the presence of the microbiota-derived TLR agonists (retentate fraction) and that it possesses anti-inflammatory potential reflected by the induction of IL-10 from THP-1 macrophages (dialysate fraction).

Original languageEnglish
JournalNutrients
Volume11
Issue number2
DOIs
Publication statusPublished - 22 Jan 2019

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Toll-Like Receptors
agonists
interleukin-10
microorganisms
metabolism
Toll-Like Receptor 4
immunosuppressive agents
Pinus pinaster
Microbiota
anti-inflammatory activity
lipopolysaccharides
cell membranes
dietary supplements
bioactive properties
bark
macrophages
Anti-Inflammatory Agents
digestion
secretion
metabolites

Keywords

  • catechin
  • gastrointestinal metabolism
  • immunomodulation
  • metabolites
  • partial agonist
  • Pycnogenol®
  • Toll-like receptors

Cite this

Verlaet, Annelies ; van der Bolt, Nieke ; Meijer, Ben ; Breynaert, Annelies ; Naessens, Tania ; Konstanti, Prokopis ; Smidt, Hauke ; Hermans, Nina ; Savelkoul, Huub F.J. ; Teodorowicz, Malgorzata. / Toll-Like Receptor-Dependent Immunomodulatory Activity of Pycnogenol®. In: Nutrients. 2019 ; Vol. 11, No. 2.
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abstract = "BACKGROUND: Pycnogenol{\circledR} (PYC), an extract of French maritime pine bark, is widely used as a dietary supplement. PYC has been shown to exert anti-inflammatory actions via inhibiting the Toll-like receptor 4 (TLR4) pathway. However, the role of the other receptors from the TLR family in the immunomodulatory activity of PYC has not been described so far. AIM: The aim of this study was to investigate whether PYC might exert its immunomodulatory properties through cell membrane TLRs (TLR1/2, TLR5, and TLR2/6) other than TLR4. Moreover, the effect of gastrointestinal metabolism on the immunomodulatory effects of PYC was investigated. FINDINGS: We showed that intact non-metabolized PYC dose-dependently acts as an agonist of TLR1/2 and TLR2/6 and as a partial agonist of TLR5. PYC on its own does not agonize or antagonize TLR4. However, after the formation of complexes with lipopolysaccharides (LPS), it is a potent activator of TLR4 signaling. Gastrointestinal metabolism of PYC revealed the immunosuppressive potential of the retentate fraction against TLR1/2 and TLR2/6 when compared to the control fraction containing microbiota and enzymes only. The dialyzed fraction containing PYC metabolites revealed the capacity to induce anti-inflammatory IL-10 secretion. Finally, microbially metabolized PYC affected the colonic microbiota composition during in vitro gastrointestinal digestion. CONCLUSIONS: This study showed that gastrointestinal metabolism of PYC reveals its biological activity as a potential inhibitor of TLRs signaling. The results suggest that metabolized PYC acts as a partial agonist of TLR1/2 and TLR2/6 in the presence of the microbiota-derived TLR agonists (retentate fraction) and that it possesses anti-inflammatory potential reflected by the induction of IL-10 from THP-1 macrophages (dialysate fraction).",
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author = "Annelies Verlaet and {van der Bolt}, Nieke and Ben Meijer and Annelies Breynaert and Tania Naessens and Prokopis Konstanti and Hauke Smidt and Nina Hermans and Savelkoul, {Huub F.J.} and Malgorzata Teodorowicz",
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Toll-Like Receptor-Dependent Immunomodulatory Activity of Pycnogenol®. / Verlaet, Annelies; van der Bolt, Nieke; Meijer, Ben; Breynaert, Annelies; Naessens, Tania; Konstanti, Prokopis; Smidt, Hauke; Hermans, Nina; Savelkoul, Huub F.J.; Teodorowicz, Malgorzata.

In: Nutrients, Vol. 11, No. 2, 22.01.2019.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Toll-Like Receptor-Dependent Immunomodulatory Activity of Pycnogenol®

AU - Verlaet, Annelies

AU - van der Bolt, Nieke

AU - Meijer, Ben

AU - Breynaert, Annelies

AU - Naessens, Tania

AU - Konstanti, Prokopis

AU - Smidt, Hauke

AU - Hermans, Nina

AU - Savelkoul, Huub F.J.

AU - Teodorowicz, Malgorzata

PY - 2019/1/22

Y1 - 2019/1/22

N2 - BACKGROUND: Pycnogenol® (PYC), an extract of French maritime pine bark, is widely used as a dietary supplement. PYC has been shown to exert anti-inflammatory actions via inhibiting the Toll-like receptor 4 (TLR4) pathway. However, the role of the other receptors from the TLR family in the immunomodulatory activity of PYC has not been described so far. AIM: The aim of this study was to investigate whether PYC might exert its immunomodulatory properties through cell membrane TLRs (TLR1/2, TLR5, and TLR2/6) other than TLR4. Moreover, the effect of gastrointestinal metabolism on the immunomodulatory effects of PYC was investigated. FINDINGS: We showed that intact non-metabolized PYC dose-dependently acts as an agonist of TLR1/2 and TLR2/6 and as a partial agonist of TLR5. PYC on its own does not agonize or antagonize TLR4. However, after the formation of complexes with lipopolysaccharides (LPS), it is a potent activator of TLR4 signaling. Gastrointestinal metabolism of PYC revealed the immunosuppressive potential of the retentate fraction against TLR1/2 and TLR2/6 when compared to the control fraction containing microbiota and enzymes only. The dialyzed fraction containing PYC metabolites revealed the capacity to induce anti-inflammatory IL-10 secretion. Finally, microbially metabolized PYC affected the colonic microbiota composition during in vitro gastrointestinal digestion. CONCLUSIONS: This study showed that gastrointestinal metabolism of PYC reveals its biological activity as a potential inhibitor of TLRs signaling. The results suggest that metabolized PYC acts as a partial agonist of TLR1/2 and TLR2/6 in the presence of the microbiota-derived TLR agonists (retentate fraction) and that it possesses anti-inflammatory potential reflected by the induction of IL-10 from THP-1 macrophages (dialysate fraction).

AB - BACKGROUND: Pycnogenol® (PYC), an extract of French maritime pine bark, is widely used as a dietary supplement. PYC has been shown to exert anti-inflammatory actions via inhibiting the Toll-like receptor 4 (TLR4) pathway. However, the role of the other receptors from the TLR family in the immunomodulatory activity of PYC has not been described so far. AIM: The aim of this study was to investigate whether PYC might exert its immunomodulatory properties through cell membrane TLRs (TLR1/2, TLR5, and TLR2/6) other than TLR4. Moreover, the effect of gastrointestinal metabolism on the immunomodulatory effects of PYC was investigated. FINDINGS: We showed that intact non-metabolized PYC dose-dependently acts as an agonist of TLR1/2 and TLR2/6 and as a partial agonist of TLR5. PYC on its own does not agonize or antagonize TLR4. However, after the formation of complexes with lipopolysaccharides (LPS), it is a potent activator of TLR4 signaling. Gastrointestinal metabolism of PYC revealed the immunosuppressive potential of the retentate fraction against TLR1/2 and TLR2/6 when compared to the control fraction containing microbiota and enzymes only. The dialyzed fraction containing PYC metabolites revealed the capacity to induce anti-inflammatory IL-10 secretion. Finally, microbially metabolized PYC affected the colonic microbiota composition during in vitro gastrointestinal digestion. CONCLUSIONS: This study showed that gastrointestinal metabolism of PYC reveals its biological activity as a potential inhibitor of TLRs signaling. The results suggest that metabolized PYC acts as a partial agonist of TLR1/2 and TLR2/6 in the presence of the microbiota-derived TLR agonists (retentate fraction) and that it possesses anti-inflammatory potential reflected by the induction of IL-10 from THP-1 macrophages (dialysate fraction).

KW - catechin

KW - gastrointestinal metabolism

KW - immunomodulation

KW - metabolites

KW - partial agonist

KW - Pycnogenol®

KW - Toll-like receptors

U2 - 10.3390/nu11020214

DO - 10.3390/nu11020214

M3 - Article

VL - 11

JO - Nutrients

JF - Nutrients

SN - 2072-6643

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Verlaet A, van der Bolt N, Meijer B, Breynaert A, Naessens T, Konstanti P et al. Toll-Like Receptor-Dependent Immunomodulatory Activity of Pycnogenol®. Nutrients. 2019 Jan 22;11(2). https://doi.org/10.3390/nu11020214