Radio‐immunoassay for formyl methionyl leucyl phenylalanine. II. Demonstration of an enterohepatic circulation of immunoreactive bacterial chemotactic peptides in man

Roberts, E. C.; Hobson, C. H.; Chadwick, V. S.

doi:10.1111/j.1440-1746.1990.tb01766.x

Cited by 17 publications

(18 citation statements)

References 5 publications

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“…In the intestinal milieu, where luminal concentrations of Nformyl peptides are at least in the micromolar range [13], the response to injury by PMN is of particular importance. Release of formyl peptides to tissues underlying the injured epithelium at such concentrations activate PMN FPR1 and may contribute to formation of intestinal crypt abscesses [14] in major acute and chronic inflammatory conditions of the intestine [15].…”

Section: Introductionmentioning

confidence: 99%

Human neutrophil formyl peptide receptor phosphorylation and the mucosal inflammatory response

Leoni

Gripentrog

Lord

et al. 2014

Journal of Leukocyte Biology

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Bacterial/mitochondrial fMLF analogs bind FPR1, driving accumulation/activation of PMN at sites of infection/injury, while promoting wound healing in epithelia. We quantified levels of UFPR1 and TFPR1 in isolated PMN by use of phosphosensitive NFPRb and phosphorylation-independent NFPRa antibodies. UFPR1 and total TFPR were assessed inflamed mucosa, observed in human IBD. In isolated PMN after fMLF stimulation, UFPR1 declined 70% ((fMLF)EC50 = 11 ± 1 nM; t1/2 = 15 s) and was stable for up to 4 h, whereas TFPR1 changed only slightly. Antagonists (tBoc-FLFLF, CsH) and metabolic inhibitor NaF prevented the fMLF-dependent UFPR1 decrease. Annexin A1 fragment Ac2-26 also induced decreases in UFPR1 ((Ac2-26)EC50 ∼ 3 µM). Proinflammatory agents (TNF-α, LPS), phosphatase inhibitor (okadaic acid), and G-protein activator (MST) modestly increased (fMLF)EC50, 2- to 4-fold, whereas PTX, Ca(2+) chelators (EGTA/BAPTA), H2O2, GM-CSF, ENA-78, IL-1RA, and LXA4 had no effect. Aggregation-inducing PAF, however, strongly inhibited fMLF-stimulated UFPR1 decreases. fMLF-driven PMN also demonstrated decreased UFPR1 after traversing monolayers of cultured intestinal epithelial cells, as did PMN in intestinal mucosal samples, demonstrating active inflammation from UC patients. Total TFPR remained high in PMN within inflamed crypts, migrating through crypt epithelium, and in the lamina propria-adjoining crypts, but UFPR1 was only observed at some peripheral sites on crypt aggregates. Loss of UFPR1 in PMN results from C-terminal S/T phosphorylation. Our results suggest G protein-insensitive, fMLF-dependent FPR1 phosphorylation in isolated suspension PMN, which may manifest in fMLF-driven transmigration and potentially, in actively inflamed tissues, except at minor discrete surface locations of PMN-containing crypt aggregates.

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Section: Introductionmentioning

confidence: 99%

Human neutrophil formyl peptide receptor phosphorylation and the mucosal inflammatory response

Leoni

Gripentrog

Lord

et al. 2014

Journal of Leukocyte Biology

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“…mFPR2 mediates the expression of proinflammatory cytokines by colonic mucosa. fMLF, a product of intestinal bacteria such as E. coli (18), is present at high (in the micromolar range) concentrations in the colon (19) and is implicated in the initiation and perpetuation of inflammatory bowel disease (IBD) (20,21). Since TNF-α, IL-1β, IL-6, and chemokines temporally and spatially orchestrate the development and progression of IBD (22), we examined the capacity of fMLF to stimulate the expression of cytokine and chemokine mRNA (23) in mouse colonic mucosa.…”

Section: Figurementioning

confidence: 99%

Formylpeptide receptor-2 contributes to colonic epithelial homeostasis, inflammation, and tumorigenesis

Chen¹,

Liu²,

Liu³

et al. 2013

J. Clin. Invest.

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Commensal bacteria and their products provide beneficial effects to the mammalian gut by stimulating epithelial cell turnover and enhancing wound healing, without activating overt inflammation. We hypothesized that N-formylpeptide receptors, which bind bacterial N-formylpeptides and are expressed by intestinal epithelial cells, may contribute to these processes. Here we report that formylpeptide receptor-2 (FPR2), which we show is expressed on the apical and lateral membranes of colonic crypt epithelial cells, mediates N-formylpeptide-dependent epithelial cell proliferation and renewal. Colonic epithelial cells in FPR2-deficient mice displayed defects in commensal bacterium-dependent homeostasis as shown by the absence of responses to N-formylpeptide stimulation, shortened colonic crypts, reduced acute inflammatory responses to dextran sulfate sodium (DSS) challenge, delayed mucosal restoration after injury, and increased azoxymethane-induced tumorigenesis. These results indicate that FPR2 is critical in mediating homeostasis, inflammation, and epithelial repair processes in the colon.

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“…0.1 µM [6], and is the major chemotactic peptide produced by E. coli [7]. In experimental animals, colonic infusions of fMLP induce colitis [8,9].…”

Section: Introductionmentioning

confidence: 99%

Interaction between bacterial peptides, neutrophils and goblet cells: a possible mechanism for neutrophil recruitment and goblet cell depletion in colitis

LEIPER¹,

Campbell²,

Jenkinson³

et al. 2001

Clinical Science

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Goblet cell depletion occurs in various forms of colitis, but its mechanism is unknown. We have investigated two linked hypotheses: (i) that bacterial peptides, such as formyl-methionyl-leucyl-phenylalanine (fMLP), interact with epithelial cells inducing the release of chemokines, including interleukin-8 (IL-8), which in turn leads to the recruitment of neutrophils which release mucin secretagogues; (ii) that fMLP acts directly on epithelial cells to cause mucus secretion. Studies were performed to measure the effects of fMLP on the synthesis and secretion of IL-8 and mucus by the goblet cell differentiated colon cancer cell lines HT29-MTX (methotrexate-conditioned HT29 colonic adenocarcinoma cell line) and LS174T, and to assess the effects of neutrophil-derived secretagogues on goblet cell secretion in these cell lines. fMLP (0.1 microM) increased the secretion of IL-8 by 105% (P<0.0001) in HT29-MTX cells and by 401% (P<0.0001) in LS174T cells. fMLP also increased the synthesis and secretion of mucins by these cell lines, with maximal effects of 65% above control values for synthesis (P<0.01) and 73% for secretion (P<0.01). A dose-related increase (up to 67%; P<0.01) in mucin secretion was demonstrated in HT29-MTX cells in response to incubation with supernatant from activated neutrophils. This effect was largely (83%; P<0.02) inhibited by ICI 200,355, a specific inhibitor of neutrophil elastase. In conclusion, the bacterial peptide fMLP and neutrophil elastase are both potent mucus secretagogues for colon epithelial cells. fMLP also elicits release of the potent neutrophil chemoattractant IL-8 from colon epithelial cells. These findings support the hypothesis that the mucosal inflammation and mucus depletion seen in ulcerative colitis could result from interaction between bacterial peptides and the mucosa.

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Radio‐immunoassay for formyl methionyl leucyl phenylalanine. II. Demonstration of an enterohepatic circulation of immunoreactive bacterial chemotactic peptides in man

Cited by 17 publications

References 5 publications

Human neutrophil formyl peptide receptor phosphorylation and the mucosal inflammatory response

Human neutrophil formyl peptide receptor phosphorylation and the mucosal inflammatory response

Formylpeptide receptor-2 contributes to colonic epithelial homeostasis, inflammation, and tumorigenesis

Interaction between bacterial peptides, neutrophils and goblet cells: a possible mechanism for neutrophil recruitment and goblet cell depletion in colitis

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