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

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).

Bovine Lactoferrin Enhances TLR7-Mediated Responses in Plasmacytoid Dendritic Cells in Elderly Women: Results From a Nutritional Intervention Study With Bovine Lactoferrin, GOS and Vitamin D.

During aging the immune system is dysregulated. Especially plasmacytoid dendritic cells (pDCs) and myeloid DCs (mDCs) have reduced Toll like receptor (TLR)-mediated responses resulting in increased susceptibility to infections. Consumption of bovine lactoferrin (bLF) has been shown to reduce infections with viruses. Galacto-oligosacharides (GOS) and vitamin D are associated with reduced pro-inflammatory cytokine levels in serum, and increased TLR7/8 responses, respectively. A double-blind placebo-controlled nutritional intervention study in elderly women was performed, to investigate the potential of bLF, GOS, and vitamin D to restore TLR responsiveness of pDCs and mDCs and to reduce inflammatory markers in serum. The nutritional intervention group (n = 15) received bLF for 3 weeks, followed by 3 weeks of bLF + GOS, and subsequently 3 weeks of bLF + GOS + vitamin D. The placebo group (n = 15) received maltodextrin for 9 weeks. Every 3 weeks, blood was collected and TLR responses of pDCs and mDCs, and inflammation-related markers in serum were measured. After 3 weeks of bLF supplementation, increased TLR7/8 and TLR1/2 responses were observed in pDCs of the nutritional intervention group compared to the placebo group. When the effects of the entire nutritional intervention were investigated, increased TLR1/2 mediated responses in mDCs were observed, and in serum sVCAM tended to decrease. Finally, based on the RAND-36 questionnaire physical function tended to improve in the intervention group. Since especially TLR7-mediated responses in pDCs were enhanced after bLF supplementation compared to placebo, this suggests that bLF may contribute to antiviral responses mediated by pDC in elderly women.Clinical trial registry number: NCT03026244, clinicaltrials.gov.