Research Report

Innate immunity

2. Substances to act on immunity

In most of the functional foods which activate immunity, microorganisms play main role such as in fermented foods made up mainly of Lactobacillus, fungi or yeast except some proteinaceous factors such as lactoferrin. In fact, the immune system of animals and plants can be activated when foreign substances such as microorganisms in the environment enter in the body in a natural way. The mechanism of this activation is called "Innate Immunity" and the details of intracellular signal transduction pathway have been made clear at molecular level during the last ten years.

Lactobacillas is a species of Gram-negative bacteria, and its effective ingredient is peptidoglycan on the cellular wall. Peptidoglycan consisit of polysaccharide and peptides (several amino acids), and has a reticulated structure with the cross-linkage in the region of the peptide. The active ingredient of immuno activation by yeasts and fungi, both of which are eukaryotes is β-glucan. β-glucan is composed of glucose linked byβ1,3 or β1,6 glycosidic linkage. In both cases, the molecular weight is some millions of daltons, when the molecule is not hydrolyzed, and their water solution show high viscosity.

On the other hand, LPS derived from Gram-negative bacteria activates innate immunity. LPS of Gram-negative bacteria have a structure of oligosaccharide unit attached to lipid, and its molecular weight ranges from five thousand to 50 thousand of daltons in ladder distribution according to the number of attached oligosaccharide unit. LPS of Pantoea agglomerans shows a distribution of molecular weight with the peaks around 5,000, and 45,000 Da. Peptidoglycan or β-glucan activates the immune cells of innate immunity through binding to TLR2 (toll-like receptor 2) and/or Dectin 1, receptors on the surface of immune cells of innate immunity, such as macrophages, which recognizes foreign substances. On the other hand, LPS also activates the immune cells through binding to another receptor called TLR4.

In this study, we compared macrophage activation by LPS (derived from Pantoea agglomerans; IP-PA1) by peptidoglycan of Lactobacillus, and by β-glucan of a ferment (derived from bread yeast).

From the result in Fig.1, LPS was shown to be superior to peptidoglycan or β-glucan as for macrophage activation. High specific activity means that a substance is effective with a small amount. In fact, in various animal experiments conducted so far, LPS showed efficacy with a small amount: 10-20 microgram/kg of body weight. On the other hand, 50-200 mg/kg body weight of β-glucan or 200 microgram/kg body weight of peptidoglycan is used in the feed for animals.

Interestingly enough, the result showed a synergistic effect of LPS in combination with peptidoglycan or with β-glucan, on macrophage activation. This result indicates a possibility to obtain a superior immuno modulatory effect by a good combination of immunoactivations which bind to TLR.

Fig.1 Synergistic effect with LPS

Fig.1

 

Fig.2 Comparison of macrophage activation activity between IP-PA1and LPS material

Fig.2

As in the example mentioned above, signals from TLR seem to have cross-talk to each other. For example, the comparison of NO production by purified LPS (derived from pantoea agglomerans; IP-PA1) and that by LPS material containing the same amount of IP-PA1 using the same experimental system as mentioned above, showed that NO production of the fermented-flour extract was about 1.7 times higher than purified IP-PA1 around the concentration of IP-PA1 at 10 microgram/ml (Fig.2).

The fermented-flour extract is a material produced by zymotechnics and contains a very small quantity of nucleic acids of Pantoea agglomerans. Bacterial CpG DNA is known to activate macrophages through binding to TLR9, another TLR receptor. DeNard et al, reported that the signal from TLR9 is enhanced synergistically by the signal from TLR4, and we consider that this phenomenon is observed with the fermented-flour extract *1.

 

*1 De Nardo, D., De Nardo, C. M., Nguyen, T., Hamilton, J. A., and Scholz, G. M., J. Immunol. 183 8110-8118 (2009)

 

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