Dendritic Cell Maturation Induced by Muramyl Dipeptide (MDP) Derivatives: Monoacylated MDP Confers TLR2/TLR4 Activation

Uehori, Junji; Fukase, Koichi; Akazawa, Takashi; Uematsu, Satoshi; Akira, Shizuo; Funami, Kenji; Shingai, Masashi; Matsumoto, Misako; Azuma, Ichiro; Toyoshima, Kumao; Kusumoto, Shoichi; Seya, Tsukasa

doi:10.4049/jimmunol.174.11.7096

Cited by 97 publications

(75 citation statements)

References 49 publications

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“…The results infer that PGN as well as GPLs participates in chicken TLR activation, the case being similar to that of BCG-cell wall, the active center of which is BCG-PGN and presumably muramyl dipeptide (15,18).…”

mentioning

confidence: 74%

Combinational recognition of bacterial lipoproteins and peptidoglycan by chicken Toll-like receptor 2 subfamily

Higuchi

Matsuo

Shingai

et al. 2008

Developmental & Comparative Immunology

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2 SummaryHuman TLR2 subfamily recognizes bacterial lipoproteins (BLP) and peptidoglycan (PGN). According to the genome information, chicken has structural orthologs of TLRs 1 and 2, in addition to TLRs3, 4, 5 and 7. Chicken has two additional TLRs, TLR15 and TLR21, which orthologs human lacks. The chicken (ch)TLR1 and 2 genes are individually duplicated to encode for two different proteins, chTLRs, chTLR1-1, 1-2, 2-1 and 2-2, of the TLR2 subfamily. Here we investigated the functional profile of these TLR2 subfamily proteins of chicken. By NF-κB reporter assay using HEK293 cells, we found that chTLR2-1 and chTLR1-2 cooperatively signal the presence of PGN. A combination of chTLR2-1 and chTLR1-2 also most efficiently recognized diacylated BLP, Malp-2, while the combination of chTLR2-1 and chTLR1-1 failed to recognize Malp-2. All combinations, however, recognized triacylated BLP, Pam3. Consistent with these results, human TLR2-stimulating mycobacteria preparations, BCG-cell wall and cell lysate of Mycobacterium avium, induced activation of NF-κB in cells expressing chTLR2-1 and 1-2 and to lesser extents, cells with chTLR2-2 and either of chTLR1. Strikingly, expression of either of these alone did not activate the reporter for NF-κB. These chTLRs are likely to have the combination functional feature as in the human TLR2 subfamily. Confocal and immunoprecipitation analyses of human cell transfectants showed that they cluster on the cell surface by a physical molecular association, causing all of them to merge and coprecipitate. These results suggest that chTLR2 subfamily members discriminate between their ligands by combinational events.

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mentioning

confidence: 74%

Combinational recognition of bacterial lipoproteins and peptidoglycan by chicken Toll-like receptor 2 subfamily

Higuchi

Matsuo

Shingai

et al. 2008

Developmental & Comparative Immunology

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“…For instance Natural Killer (NK) cells, which belong to Group 1 ILCs and attend in the gut homeostasis by responding to commensally enteric bacteria through the innate immune system and cytolytic activity, express high levels of NOD2 [106], and MDP treatment of these cells leads directly to cell activation through the NOD2-mediated pathway [107]. In addition, MDP can also be sensed by TLR2 (described below) [108,109] which is expressed on RORγt + ILCs [110]. Therefore, MDP might have an indirectly influence on ILCs through modulation of other cellular components of the innate immunity.…”

Section: Listeria Monocytogenes Citrobacter Rodentium Salomonella Amentioning

confidence: 99%

“…Beyond the ability to activate NOD2-mediated signaling pathways, MDP can interact and signal through TLR2 [108,109] . TLR2 recognizes MDP and activates NEMO-NF-κB pathway through two independently upstream signaling pathways [120].…”

Section: Cross-talk Between Nod2 and Other Innate Pathwaysmentioning

confidence: 99%

Muramyl dipeptide responsive pathways in Crohn’s disease: from NOD2 and beyond

Salem

Seidelin

Rogler

et al. 2012

Cell. Mol. Life Sci.

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Crohn's disease (CD) is one of main disease entities under the umbrella term chronic inflammatory bowel disease. The etiology of CD involves alterations in genetic, microbiological, and immunological factors. This review is devoted to the role of the bacterial wall compound muramyl dipeptide (MDP) for the activation of inflammatory pathways involved in the pathogenesis of CD. The importance of this molecule is underscored by the fact that (1) MDP, which is found in most Gram-negative and -positive bacteria, is able to trigger several immunological responses in the intestinal system, and (2) that alterations in several mediators of the MDP response including-but not restricted to-nucleotide oligomerization domain 2 (NOD2) are associated with CD. The normalization of MDP signaling is one of several important factors that influence the intestinal inflammatory response, a fact which emphasizes the pathogenic importance of MDP signaling for the pathogenesis of CD. The important aspects of NOD2 and non-NOD2 mediated effects of MDP for the development of CD are highlighted, as well as how alterations in these pathways might translate into the development of new therapeutic strategies.

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“…2A). Since interaction between NOD2 and specific TLR pathways has been reported as a mechanism of cooperation in the innate immune response, which might lead to the synergistic activation of host cells [24][25][26], the effect of the combined addition of both Staphylococcus aureus PGN and MDP was assessed. As shown in Fig.…”

Section: Pamp Signatures Are Strong Inducers Of Cox-2 Protein In Humamentioning

confidence: 99%

Mannan and peptidoglycan induce COX‐2 protein in human PMN via the mammalian target of rapamycin

et al. 2007

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The induction of cyclooxygenase-2 (COX-2) protein expression was assessed in human polymorphonuclear leukocytes (PMN) stimulated via receptors of the innate immune system. Peptidoglycan (PGN) and mannan, and at a lower extent the bacterial lipoprotein mimic palmitoyl-3-cysteine-serine-lysine-4, induced COX-2 protein expression. In contrast, lipoteichoic acid and muramyldipeptide were irrelevant stimuli. The mRNA encoding COX-2 was present in resting PMN at an extent quite similar to that detected in stimulated PMN, whereas the expression of COX-2 protein was undetectable. Treatment with the phosphatidylinositol 3-kinase inhibitor (PI3K) wortmaninn, the mammalian target of rapamycin (mTOR) inhibitor rapamycin, and the translation inhibitor cycloheximide blocked the induction of COX-2 protein in response to mannan and PGN, whereas the transcriptional inhibitor actinomycin D did not show a significant effect. These results disclose a capability of pathogen-associated molecular patterns to induce the oxidative metabolism of arachidonic acid more robust than that of PMN archetypal chemoattractants, since mannan and PGN make it coincidental the release of arachidonic acid with a rapid induction of COX-2 protein regulated by a signaling cascade involving PI3K, mTOR, and the translation machinery. This mechanism of COX-2 protein induction expression in PMN is substantially different from that operative in mononuclear phagocytes, which is highly dependent on transcriptional regulation. IntroductionPMN are essential elements of the innate immune system due to their wide predominance in peripheral blood and their rapid mobilization into tissues in response to microbial infection. PMN can be activated by a variety of stimuli, which includes cytokines, IgG class antibodies, complement factors, extracellular matrix components, adhesion molecules, and microorganism constituents. This group of stimuli is of chief importance, since early protection against pathogens relies on the recognition by phagocytes of unique pattern molecules, termed pathogen-associated molecular patterns (PAMP), which are recognized through pattern-recognition receptors (PRR) by the host innate immune system. The TLR family (for review see [1, 2]), the nucleotide-binding oligomerization domain (NOD) family proteins (for review see [3][4][5]), the lectin C-type receptors such as the b-glucan receptor dectin-1 [6], and the mannose receptor (MR) family (for review see [7, 8]) include a wide array of PRR able to interact with many structural signatures expressed in microorganisms.The study of the response of PMN to PAMP has focused on the induction of cytokines, the activation of oxidant production, the release of granular components, and the modulation of apoptosis [9][10][11]. However, few data are available regarding the activation of the arachidonic acid (AA) cascade, yet this seems of interest in view of the important role of eicosanoids in connecting innate and adaptive immunity [12][13][14][15] and the attention paid to the pharmacological modulation ...

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Dendritic Cell Maturation Induced by Muramyl Dipeptide (MDP) Derivatives: Monoacylated MDP Confers TLR2/TLR4 Activation

Cited by 97 publications

References 49 publications

Combinational recognition of bacterial lipoproteins and peptidoglycan by chicken Toll-like receptor 2 subfamily

Combinational recognition of bacterial lipoproteins and peptidoglycan by chicken Toll-like receptor 2 subfamily

Muramyl dipeptide responsive pathways in Crohn’s disease: from NOD2 and beyond

Mannan and peptidoglycan induce COX‐2 protein in human PMN via the mammalian target of rapamycin

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