title: Muropeptides trigger distinct activation profiles in macrophages and dendritic cells.
abstract: Bacterial peptidoglycan and its muropeptide derivatives potently activate mammalian innate immune system and are promising immunomodulators and vaccine adjuvants. However, their effects on human antigen-presenting cells, such as dendritic cells (DCs) and Mphi, are not fully understood. Lysozyme treatment of PG from Salmonella typhi yielded three muropeptides, GlcNAc-MurNAc-L-Ala-D-isoGlu-meso-DAP (GM-3P), GlcNAc-MurNAc-L-Ala-D-isoGlu-meso-DAP-D-Ala (GM-4P), and a dimer (GM-4P)(2), in which two GM-4P monomers are linked through their peptidic moieties. All three muropeptides induced TNF-alpha and IL-6 production by Mphi (GM-3P>GM-4P>>(GM-4P)(2)), but failed to trigger TNF-alpha, IL-6 and IL-12p70 production by immature DCs. At the same time, muropeptide-stimulated DCs abundantly produced inflammatory chemokines IL-8, MIP-1 alpha and MIP-1 beta, as well as displayed signs of phenotypic and functional maturation. Thus, muropeptide-dependent pro-inflammatory cytokine production is repressed in DCs. While this defect may be partly compensated in vivo by muropeptide-activated Mphi, neither Mphi nor DCs produce Th1- or Th17-polarizing cytokines upon muropeptide stimulation, which may contribute to the preferential induction of Th2 responses by muropeptides and should be taken into account when designing muropeptide-based immunomodulators and adjuvants.
authors.affiliation: National Research Center Institute of Immunology, Kashirskoe shosse 24, bldg 2, 115478 Moscow, Russia. mvpashenkov@yandex.ru
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Pashenkov
authors.forename: Sergei F
authors.initials: SF
authors.lastname: Popilyuk
authors.forename: Biana I
authors.initials: BI
authors.lastname: Alkhazova
authors.forename: Vyacheslav L
authors.initials: VL
authors.lastname: L'vov
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Murugin
authors.forename: Elena S
authors.initials: ES
authors.lastname: Fedenko
authors.forename: Rakhim M
authors.initials: RM
authors.lastname: Khaitov
authors.forename: Boris V
authors.initials: BV
authors.lastname: Pinegin
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006020:Glycopeptides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D006801:Humans; D056747:Immunomodulation; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D053474:Nod1 Signaling Adaptor Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010457:Peptidoglycan / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D012485:Salmonella typhi; D018417:Th1 Cells / Q000276:immunology; D058408:Th1-Th2 Balance; D018418:Th2 Cells / Q000276:immunology
chemical_list: D016207:Cytokines; C556230:GlcNAc-MurNAc-Ala-isoGlu-DAP; C556231:GlcNAc-MurNAc-Ala-isoGlu-DAP-Ala; D006020:Glycopeptides; C119067:NOD1 protein, human; C429018:NOD2 protein, human; D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein; D010457:Peptidoglycan