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Kaji et al (2010) Bacterial teichoic acids reverse predominant IL-12 production induced by certain Lactobacillus strains into predominant IL-10 production via TLR2-dependent ERK activation in macrophages

Kaji et al (2010) Bacterial teichoic acids reverse predominant IL-12 production induced by certain Lactobacillus strains into predominant IL-10 production via TLR2-dependent ERK activation in macrophages

Citation

Kaji R, Kiyoshima-Shibata J, Nagaoka M, Nanno M, Shida K (2010) Bacterial teichoic acids reverse predominant IL-12 production induced by certain Lactobacillus strains into predominant IL-10 production via TLR2-dependent ERK activation in macrophages. Journal of Immunology 184: 3505-3513.

Background

There are indications that the cytokine response of macrophages to probiotic lactobacilli is strain-dependent. The IL-10/IL-12 ratio is important in determining the direction of the immune response.

Mitogen-activated protein kinases (MAPKs) are enzymes that respond to different stimuli to regulate various cellular processes, such as cell differentiation, gene expression and mitosis. MAPK activation is a key signal transduction event involved in control of cytokine production.

Objective

To further elucidate the mechanisms of lactobacilli stimulated IL-10 and IL-12 production by analysis of MAPK activation in mouse peritoneal macrophages.

Methods

Different in vitro experimental methods were used to investigate the effect of lactobacilli on mouse peritoneal macrophages. Three strains were used: Lactobacillus casei Shirota (LcS), L. johnsonii JCM 2012 and L. plantarum ATCC 14917. The tests investigated both whole cells and cell components (polysaccharide-peptidoglycan complex, protoplast, intact cell wall, lipoteichoic acid), and involved flow cytometric analysis of phagocytosis, microscopic analysis of macrophage lysis of the phagocytosed lactobacilli, macrophage IL-10 and IL-12 production, expression of cytokine mRNA in the macrophages, cytokine determination by ELISA.

The lactobacilli stimulation of particular MAPK pathways involved in cytokine production was measured by Western blot analysis, including selective blockade of ERK, p38 and JNK activation to investigate the involvement of the particular molecules in cytokine production.

The influence of cell wall components on the macrophage secretion of IL-10 was studied by ELISA and Western blot.

Results

The L. plantarum strain was the strongest inducer of IL-10 production in the mouse peritoneal macrophages, and only weakly induced IL-12 production. In contrast, LcS strongly induced IL-12 and weakly induced IL-10.

The strains also showed different degrees of MAPK pathways stimulation: L. plantarum was a strong activator of ERK and JNK, while L. casei and L. johnsonii were weaker. The three lactobacilli showed a similar degree of p38 pathway activation. The susceptibility to macrophage digestion appeared to be related to the time course of MAPK phosphorylation: L. plantarum was a faster and stronger inducer of MAPKs activation compared to LcS; with LcS (the most resistant to digestion) activation peaked later but was maintained at a high level over a longer period.

All three MAPK pathways (ERK, p38, JNK) were shown to be important for IL-10 production but only the ERK pathway was critical for determining the IL-10/IL-12 production balance. IL-10 production was induced synergistically when the macrophages were stimulated with a combination of LcS and the L. plantarum strain, or LcS and teichoic acids. Tests with the different cell wall components showed that teichoic acids were recognized by toll-like receptor 2 (TLR-2) expressed by the macrophages, which activated the ERK pathway.

Conclusions

This study shows that activation of the ERK pathway, triggered by recognition of teichoic acid by macrophage-expressed TLR2, is a key step in determining the IL-10/IL-12 balance from macrophages responding to lactobacilli stimulation. The data indicate that the predominantly IL-12 response induced by LcS can change to a predominantly IL-10 response in the presence of teichoic acids. The authors speculated that this could explain how LcS can enhance immune defences (as shown in human studies for cancer, infection and allergy), as well as having beneficial effects human studies for inflammatory and autoimmune diseases.

 
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