Peptidoglycan from lactobacilli inhibits interleukin-12 production by macrophages induced by Lactobacillus casei through Toll-like receptor 2-dependent and independent mechanisms.
We previously showed that Lactobacillus strains having a rigid cell wall resistant to intracellular digestion can stimulate macrophages to induce large a quantity of interleukin-12 (IL-12). In this study, we examined the influence of lactobacilli and bacterial cell wall components on IL-12 production by macrophages that was induced by Lactobacillus casei, which has a rigid cell wall. Easily digestible lactobacilli such as Lactobacillus johnsonii and Lactobacillus plantarum or their intact cell walls (ICWs) weakly or very weakly induced IL-12 production by macrophages, and inhibitedL. casei-induced IL-12 production. While the ICW of L. casei was resistant to intracellular digestion and did not inhibit L. casei-induced IL-12 production, its polysaccharide-depleted ICW, i.e. intact peptidoglycan, was sensitive to intracellular digestion and inhibited L. casei-induced IL-12 production. Furthermore, the peptidoglycans of L. johnsonii, L. plantarum and Staphylococcus aureus also inhibited L. casei-induced IL-12 production. Peptidoglycans from lactobacilli suppressed L. casei-induced expression of IL-12p40 but not IL-12p35 mRNA. Inhibition of IL-12 production by peptidoglycan was mitigated in Toll-like receptor 2 (TLR2)-deficient macrophages compared with the inhibition in wild-type macrophages. A derivative of the minimal structural unit of peptidoglycan (6-O-stearoyl-muramyl dipeptide) recognized by nucleotide-binding oligomerization domain 2 (NOD2) could also suppress L. casei-induced IL-12 production. These findings demonstrate that easily digestible bacteria and peptidoglycan suppress IL-12 production through pattern recognition receptors such as TLR2 and NOD2. IL-12 production in the gut may be negatively regulated by the simultaneous inhibitory actions of various resident bacteria that are susceptible to intracellular digestion.
Shida
Kan
K
Yakult Central Institute for Microbiological Research, Tokyo, Japan. kan-shida@yakult.co.jp
Kiyoshima-Shibata
Junko
J
Kaji
Rumi
R
Nagaoka
Masato
M
Nanno
Masanobu
M
D000818:Animals; D002473:Cell Wall / Q000276:immunology*; D002478:Cells, Cultured; D005260:Female; D006026:Glycoside Hydrolases / Q000494:pharmacology; D007108:Immune Tolerance; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D053765:Interleukin-12 Subunit p35 / Q000819:agonists / Q000276:immunology; D053762:Interleukin-12 Subunit p40 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007780:Lacticaseibacillus casei / Q000187:drug effects / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D053473:Nod2 Signaling Adaptor Protein / Q000378:metabolism; D010457:Peptidoglycan / Q000276:immunology*; D010587:Phagocytosis / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000819:agonists / Q000276:immunology / Q000378:metabolism
D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; D053473:Nod2 Signaling Adaptor Protein; D010457:Peptidoglycan; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D006026:Glycoside Hydrolases; C026255:endo-N-acetylmuramidase