title: Meso-diaminopimelic acid and meso-lanthionine, amino acids specific to bacterial peptidoglycans, activate human epithelial cells through NOD1.
abstract: Peptidoglycans (PGNs) are ubiquitous constituents of bacterial cell walls and exhibit various immunobiological activities. Two types of minimum essential PGN structures for immunobiological activities were chemically synthesized and designated as muramyldipeptide; N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) and gamma-D-glutamyl-meso-diaminopimelic acid (iE-DAP), which are common constituents of both Gram-positive and Gram-negative bacteria, as well as most Gram-negative and some Gram-positive bacteria, respectively. Recently, intracellular receptors for MDP and iE-DAP have been demonstrated to be nucleotide-binding oligomerization domain (NOD)1 and NOD2, respectively. In this study, we demonstrated that chemically synthesized meso-DAP itself activated human epithelial cells from various tissues, through NOD1 to generate antibacterial factors, PGN recognition proteins and beta-defensin 2, and cytokines in specified cases, although the activities of meso-DAP were generally weaker than those of known NOD agonists. However, stereoisomers of meso-DAP, LL-DAP, and DD-DAP were only slightly activated or remained inactive, respectively. Synthetic meso-lanthionine, which is another diamino-type amino acid specific to PGN of the specified Gram-negative bacteria, was also recognized by NOD1. In human monocytic cells, in the presence of cytochalasin D meso-DAP induced slightly but significantly increased production of cytokines, although the cells did not respond to meso-DAP in the absent of cytochalasin D. Our findings suggest that NOD1 is a special sentinel molecule, especially in the epithelial barrier, allowing the intracellular detection of bacteria through recognizing meso-DAP or comparable moiety of PGN from specified bacteria in cooperation with NOD2, thereby playing a key role in innate immunity.
authors.affiliation: Department of Microbiology and Immunology, Tohoku University Graduate School of Dentistry, Sendai, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Uehara
authors.forename: Yukari
authors.initials: Y
authors.lastname: Fujimoto
authors.forename: Akiko
authors.initials: A
authors.lastname: Kawasaki
authors.forename: Shoichi
authors.initials: S
authors.lastname: Kusumoto
authors.forename: Koichi
authors.initials: K
authors.lastname: Fukase
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Takada
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D000409:Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D001407:Bacillus / Q000276:immunology; D002460:Cell Line; D045744:Cell Line, Tumor; D003352:Corynebacterium / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D003960:Diaminopimelic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D006367:HeLa Cells; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009061:Mouth Mucosa / Q000166:cytology / Q000276:immunology* / Q000382:microbiology; D009161:Mycobacterium / Q000276:immunology; D053474:Nod1 Signaling Adaptor Protein; D010457:Peptidoglycan / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000494:pharmacology; D013237:Stereoisomerism; D013440:Sulfides / Q000138:chemical synthesis / Q000494:pharmacology*; D015854:Up-Regulation / Q000276:immunology; D023083:beta-Defensins / Q000096:biosynthesis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; C106641:DEFB4A protein, human; D018836:Inflammation Mediators; C119067:NOD1 protein, human; D053474:Nod1 Signaling Adaptor Protein; D010457:Peptidoglycan; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013440:Sulfides; D023083:beta-Defensins; D003960:Diaminopimelic Acid; D007371:Interferon-gamma; C001520:lanthionine; D000409:Alanine