title: Enhancement of endotoxin activity by muramyldipeptide.
abstract: Synthetic muramyldipeptide (MDP), the minimum structural moiety of bacterial peptidoglycan for adjuvant and related activities, sensitized mice for two types of lethal shock induced by lipopolysaccharide (LPS): an early anaphylactoid shock and late endotoxin shock. In relation to the late reaction in MDP-primed mice, enhanced production of inflammatory cytokines was induced in response to various bacterial components. MDP showed a priming effect in mice not only when administered parentally but also via the oral route. MDP activated human monocytic THP-1 cells in a CD14-, Toll-like receptor 2 (TLR2)- and TLR4-independent manner to increase expression of MyD88, a common adaptor and signaling molecule for TLRs, and exhibited synergistic cytokine inducing effects with TLR4 agonists (LPS, synthetic lipid A), TLR2 agonist (synthetic lipopeptide), and TLR9 agonist (bacterial CpGDNA) in THP-1 cells in culture. Consistent with these findings, MDP primed TLR2 knockout mice as well as wild-type controls, but not TLR4-mutated C3H/HeJ mice, to enhance production of tumor necrosis factor-alpha upon stimulation with synthetic lipid A. In contrast to the BCG- and Propionibacterium acnes-priming system, MDP primed mice in an interferon-gamma-independent manner. Further studies are required to elucidate the mechanisms of the synthetic and priming activities of MDP for various bacterial components.
authors.affiliation: Department of Microbiology and Immunology, Tohoku University School of Dentistry, Sendai, Japan. dent-ht@mail.cc.tohoku.ac.jp
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Takada
authors.forename: Shigekuni
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Shuhua
authors.initials: S
authors.lastname: Yang
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D002478:Cells, Cultured; D004347:Drug Interactions; D004357:Drug Synergism; D004731:Endotoxins / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D008050:Lipid A / Q000494:pharmacology; D018950:Lipopolysaccharide Receptors / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88; D010457:Peptidoglycan / Q000737:chemistry; D011956:Receptors, Cell Surface / Q000502:physiology; D011971:Receptors, Immunologic / Q000378:metabolism; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D004731:Endotoxins; D016209:Interleukin-8; D008050:Lipid A; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D010457:Peptidoglycan; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C495371:TLR9 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D000119:Acetylmuramyl-Alanyl-Isoglutamine