PepT1-mediated fMLP transport induces intestinal  inflammation in vivo

Buyse, Marion; Tsocas, Annick; Walker, Francine; Merlin, Didier; Bado, André

doi:10.1152/ajpcell.00186.2002

Cited by 69 publications

(68 citation statements)

References 20 publications

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“…fMLP transport inhibition in the presence of other PepT1 substrates has been well described (5,11,12). In this study, exposure of gut segments to fMLP resulted in greater concentrations of proinflammatory cytokines compared to control conditions, while coperfusion with cysteinyl-glycine attenuated this response as demonstrated by lower mucosal TNF-α concentrations.…”

Section: Discussionsupporting

confidence: 58%

“…Previous studies have investigated MPO activity in response to fMLP in the small intestine and colon of rats (5,12). These investigations demonstrated that exposure to fMLP stimulated MPO activity in the small intestine, and only in colonic tissue of rats with PepT1 expression induced by small bowel resection.…”

Section: Articles Nosworthy and Bruntonmentioning

confidence: 99%

“…Further, the presence of fMLP induced neutrophil migration across an epithelial monolayer, an activity that was abolished if fMLP uptake was inhibited. PepT1-mediated transport of fMLP has also been demonstrated using in vivo rat models (12,13). In particular, uptake of fMLP has been investigated in rats using an intestinal perfusion approach (12).…”

mentioning

confidence: 99%

“…PepT1-mediated transport of fMLP has also been demonstrated using in vivo rat models (12,13). In particular, uptake of fMLP has been investigated in rats using an intestinal perfusion approach (12). Marked inflammatory response occurred in jejunal segments perfused with fMLP, an intestinal position known to have high expression of PepT1.…”

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confidence: 99%

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Cysteinyl-glycine reduces mucosal proinflammatory cytokine response to fMLP in a parenterally-fed piglet model

Nosworthy

Brunton

2016

Pediatr Res

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Background: PepT1 transports dietary and bacterial peptides in the gut. We hypothesized that cysteinyl-glycine would ameliorate the inflammatory effect of a bacterial peptide, formylmethionyl-leucyl-phenylalanine (fMLP), in both sow-fed and parenterally-fed piglets. Methods: An intestinal perfusion experiment was performed in piglets (N = 12) that were sow-reared or provided with parenteral nutrition (PN) for 4 d. In each piglet, five segments of isolated intestine were perfused with five treatments including cysteine and glycine, cysteinyl-glycine, fMLP, free cysteine and glycine with fMLP, or cysteinyl-glycine with fMLP. Mucosal cytokine responses and intestinal morphology was assessed in each gut segment. results: PN piglets had lower mucosal IL-10 by approximately 20% (P < 0.01). Cysteinyl-glycine lowered TNF-α response to fMLP in PN-fed animals and IFN-γ response to fMLP in both groups (P < 0.05). The free cysteine and glycine treatment reduced TNF-α in sow-fed animals (P < 0.05). fMLP affected villus height in parenterally (P < 0.05), but not sow-fed animals. conclusion: Parenteral feeding conferred a susceptibility to mucosal damage by fMLP. The dipeptide was more effective at attenuating the inflammatory response to a bacterial peptide than free amino acids. This may be due to competitive inhibition of fMLP transport or a greater efficiency of transport of dipeptides. t he products of protein digestion that are absorbed by the small intestinal epithelium include free amino acids and small peptides of two to three residues in length. These di/tripeptides are removed from the nutrient rich intestinal lumen by a H + /peptide symporter, peptide transporter 1 or PepT1 (1). This transporter is localized to the apical surface of the intestinal villi and has broad substrate specificity. Potential substrates for PepT1 include almost all possible dietary di/ tripeptides (1), some antibiotics (2-4) and proinflammatory bacterial peptides (5-8).The primary neutrophil chemotactic substance produced by Escherichia coli is formyl-methionyl-leucyl-phenylalanine (fMLP) (9). This tripeptide is the most predominant N-formylated peptide present in the colonic lumen of humans (9).PepT1-mediated transport of fMLP has been demonstrated in cell culture where uptake of fMLP was inhibited by the presence of known substrates of PepT1 (10,11). Further, the presence of fMLP induced neutrophil migration across an epithelial monolayer, an activity that was abolished if fMLP uptake was inhibited. PepT1-mediated transport of fMLP has also been demonstrated using in vivo rat models (12,13). In particular, uptake of fMLP has been investigated in rats using an intestinal perfusion approach (12). Marked inflammatory response occurred in jejunal segments perfused with fMLP, an intestinal position known to have high expression of PepT1. This inflammation was accompanied by an increase in DNA binding by NFκβ, a transcription factor involved in the regulation of proinflammatory cytokines. This transcription factor is capable of inducing transcri...

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Section: Discussionsupporting

confidence: 58%

Section: Articles Nosworthy and Bruntonmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Cysteinyl-glycine reduces mucosal proinflammatory cytokine response to fMLP in a parenterally-fed piglet model

Nosworthy

Brunton

2016

Pediatr Res

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“…4 Indeed, we recently demonstrated that hPepT1-mediated fMLP uptake can induce intestinal inflammation in vitro and in vivo. 11 The absorbed fMLP ultimately moves across the basolateral membrane and/or diffuses passively across the tight junctions to the lamina propria, where it may activate immune cells through specific receptors. 12 Regulation of the transcellular and paracellular movement of fMLP across the epithelium will modulate fMLP concentration in the lamina propria.…”

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hPepT1 mediates bacterial tripeptide fMLP uptake in human monocytes

Charrier

Driss

Yan

et al. 2006

Laboratory Investigation

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Here, we examined hPepT1 expression in the monocytic cell line, KG-1. Reverse transcription polymerase chain reaction (RT-PCR) analysis revealed that hPepT1 is expressed in KG-1 cells, while cDNA cloning and direct sequencing confirmed the sequence of KG-1 hPepT1 (accession number, AY634368). Immunoblotting of cell lysates from KG-1 cells or macrophages isolated from human peripheral blood revealed a B100 kDa immunoreactive band mainly present in the membrane fraction. Uptake experiments showed that the transport of 20 lM radiolabeled Gly-Sarcosine ([ 14 C]Gly-Sar) in KG-1 cells was Na þ , Cl À dependent and disodium 4,4 0 -diisothiocyanatostilbene-2,2 0 -disulfonate (DIDS)-sensitive. In addition, hPepT1 activity was likely to be coupled to a Na þ /H þ exchanger, as evidenced by the fact that [ 14 C]Gly-Sar uptake was not affected by the absence of Na þ when cells were incubated at low pH (5.2). Interestingly, hPepT1-mediated transport was reduced in KG-1 cells incubated at low pH as it was also observed in nonpolarized Caco2-BBE cells. This pattern of pH-dependence is due to a disruption of the driving force of hPepT1-mediated transport events. This was supported by our finding that nonpolarized cells, Caco2-BBE cells and KG-1 cells, have an increased permeability to H þ when compared to polarized Caco2-BBE cells. Finally, we showed that hPepT1 is responsible for transporting fMLP into undifferentiated and differentiated (macrophage-like) KG-1 cells. Together, these results show that hPepT1 is expressed in nonpolarized immune cells, such as macrophages, where the transporter functions best at the physiological pH 7.2. Furthermore, we provide evidence for hPepT1-mediated fMLP transport, which might constitute a novel immune cell activation pathway during intestinal inflammation.

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