A proinflammatory peptide from Helicobacter pylori activates monocytes to induce lymphocyte dysfunction and apoptosis

Betten, Åsa; Bylund, Johan; Cristophe, Thierry; Boulay, François; Romero, Ana I.; Hellstrand, Kristoffer; Dahlgren, Cláes

doi:10.1172/jci200113430

Cited by 37 publications

(43 citation statements)

References 33 publications

(150 reference statements)

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“…We thus identified this N-formylated peptide of mitochondrial origin as a novel low-affinity agonist for FPRL2, a receptor which was, so far, considered as refractory to activation by Nformylated peptides. There are already a few FPRL1 ligands, such as peptides derived from the bacteria H. pylori [15] and the human neuroprotective factor, humanin [12], which also binds FPRL2 with low affinity. Interestingly, the N-formylated form of humanin was found to perform more potently as a ligand for FPRL1 than non-formylated humanin, and to be chemotactic for CHO cells expressing FPRL1 or FPRL2 [36].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, FPRL1 has emerged as a promiscuous receptor, also activated by the pathogenderived peptide Hp (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) from Helicobacter pylori, by host-derived proteins and peptides such as Ac1-25 from annexin 1, cathelicidin LL37, a fragment of the urokinase receptor, the serum amyloid A, the amyloid b peptide (Ab42), the prion protein fragment PrP(106-126), the neuroprotective peptide humanin, and by different synthetic peptides including the hexapeptide Trp-LysTyr-Met-Val-D-Met-NH 2 (WKYMVm) [11,12]. FPRL2 does not respond to fMLF [13], but instead is activated by some non-formylated chemotactic peptides identified as agonists for FPRL1 [14,15]. Recently, an acetylated Nterminal peptide derived from the human heme-binding protein has been identified as a ligand specific for FPRL2 [16].…”

Section: Introductionmentioning

confidence: 99%

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Human mitochondria-derivedN-formylated peptides are novel agonists equally active on FPR and FPRL1, whileListeria monocytogenes-derived peptides preferentially activate FPR

2005

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N-formyl peptides are cleavage products of bacterial and mitochondrial proteins, and can attract leukocytes to sites of infection or tissue damage. In this study, HL-60 cell lines expressing the human N-formyl peptide receptor FPR or its two homologues (FPRL1, FPRL2) were used to determine the receptor selectivity of N-formylated peptides derived from Listeria monocytogenes or from human mitochondrial proteins. Bacterial peptides were 100-fold more potent on FPR than on FPRL1, whereas none of them could trigger intracellular signaling through FPRL2. In contrast, N-formylated hexapeptides corresponding to the N terminus of mitochondrial NADH dehydrogenase subunits 4 (fMLKLIV) and 6 (fMMYALF), and cytochrome c oxidase subunit I (fMFADRW) were equally potent on FPR and FPRL1. They triggered cellular responses with the following order of potency: fMMYALF > fMLKLIV > fMFADRW, with an EC 50 , in a Fura-2 calcium mobilization assay, of 10 nM, 44 nM, and 160 nM on FPRexpressing cells, and 15 nM, 55 nM and 120 nM on FPRL1-expressing cells. fMMYALF was also a low-affinity agonist of FPRL2 (EC 50 of 1 lM) and was chemotactic for both FPRL1-and FPRL2-expressing cells. We identified novel mitochondrial host-derived agonists for human N-formyl-peptide receptors that might play a role in inflammatory or degenerative processes linked to their stimulation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Human mitochondria-derivedN-formylated peptides are novel agonists equally active on FPR and FPRL1, whileListeria monocytogenes-derived peptides preferentially activate FPR

2005

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“…Helicobacter pylori-derived peptide Hp(2-20) binds FPRL2 and activates monocytes, and thus induces lymphocyte dysfunction and apoptosis (34). Thus we attempted to investigate whether a pathogen-derived FPRL2 agonist would also inhibit LPS-induced MoDC maturation.…”

Section: Both Fpr and Fprl2 Are Involved In The Wkymvm-induced Inhibimentioning

confidence: 99%

The Synthetic Peptide Trp-Lys-Tyr-Met-Val-D-Met Inhibits Human Monocyte-Derived Dendritic Cell Maturation via Formyl Peptide Receptor and Formyl Peptide Receptor-Like 2

Kang¹,

Lee

Kim

et al. 2005

The Journal of Immunology

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Trp-Lys-Tyr-Met-Val-D-Met (WKYMVm) has been reported to stimulate monocytes, neutrophils, and dendritic cells (DCs). However, although WKYMVm has been reported to function as a DC chemoattractant, its role on DC maturation has not been examined. In this study, we investigated the effects of WKYMVm on human DC maturation. The costimulation of DCs with WKYMVm and LPS dramatically inhibited LPS-induced IL-12 production, CD86 and HLA-DR surface expression, and DC-mediated T cell proliferation. However, DC phagocytic activity was increased by WKYMVm stimulation. These findings demonstrate that WKYMVm inhibits DC maturation by LPS. In terms of the mechanism underlying DC maturation inhibition by WKYMVm, we found that LPS-induced DC maturation was negatively regulated by WKYMVm-stimulated ERK activity. Moreover, the costimulation of DCs with WKYMVm and LPS dramatically inhibited the LPS-induced accumulations of IL-12 mRNA, thus suggesting that WKYMVm inhibits LPS-induced IL-12 production at the transcriptional level. We also found that DCs express two WKYMVm receptors, formyl peptide receptor (FPR) and FPR-like 2 (FPRL2). In addition, formyl-Met-Leu-Phe (a FPR ligand), Trp-Lys-Tyr-Met-Val-Met, Hp(2–20) peptide, and F2L (three FPRL2 ligands) inhibited LPS-induced IL-12 production in DCs. Taken together, our findings indicate that the activations of FPR and FPRL2 inhibit LPS-induced DC maturation, and suggest that these two receptors should be regarded as important potential therapeutic targets for the modulation of DC maturation.

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“…Exopolysaccharides from Burkholderia cenocepacia and alginate from Pseudomonas aeruginosa inhibit neutrophil chemotaxis and scavenge reactive oxygen species (35)(36)(37). H. pylori was found to induce the production of reactive oxygen intermediates by different elements, such as H. pylori neutrophil-activating protein (HP-NAP) (38), H. pylori lipopolysaccharide (39), or a cecropin-like H. pylori peptide Hp(2-20) (40,41), through activating NADPH-oxidase in different cells. In addition, HP-NAP was found to induce an increase of cytosolic calcium concentration in a dosedependent manner (38), which is required for eNOS activity as an NADPH oxidase.…”

Section: Discussionmentioning

confidence: 99%

H. pylori Escape Host Immunoreaction Through Inhibiting ILK Expression by VacA

Yuan

Tao

et al. 2009

Cell Mol Immunol

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Helicobacter pylori (H. pylori) persistently colonizes the gastric mucosa despite a vigorous immune response. Vacuolating cytotoxin secreted by H. pylori has turned out to be a potent immunomodulatory toxin, but the signal transduction pathways involved has not been studied in macrophages. We observed in this study that vacA-deficient H. pylori induced significantly higher expression of integrin-linked kinase (ILK) and endothelial nitric oxygen synthase (eNOS), and significantly more production of reactive oxygen species (

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A proinflammatory peptide from Helicobacter pylori activates monocytes to induce lymphocyte dysfunction and apoptosis

Cited by 37 publications

References 33 publications

Human mitochondria-derivedN-formylated peptides are novel agonists equally active on FPR and FPRL1, whileListeria monocytogenes-derived peptides preferentially activate FPR

Human mitochondria-derivedN-formylated peptides are novel agonists equally active on FPR and FPRL1, whileListeria monocytogenes-derived peptides preferentially activate FPR

The Synthetic Peptide Trp-Lys-Tyr-Met-Val-D-Met Inhibits Human Monocyte-Derived Dendritic Cell Maturation via Formyl Peptide Receptor and Formyl Peptide Receptor-Like 2

H. pylori Escape Host Immunoreaction Through Inhibiting ILK Expression by VacA

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