A 10-residue peptide from durum wheat promotes a shift from a Th1-type response toward a Th2-type response in celiac disease

Silano, Marco; Benedetto, Rita Di; Maialetti, Francesca; Vincenzi, A. De; Calcaterra, Roberta; Trecca, Antonello; Vincenzi, Massimo De

doi:10.1093/ajcn/87.2.415

Cited by 25 publications

(6 citation statements)

References 40 publications

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“…The PT-Gly contains some gliadin peptides that show different toxic activity in CD patients tissues. The alcohol-soluble protein fraction from whole cereal flour of bread wheat ( Triticum aestivum , variety S Pastore) was extracted and subjected to peptic-tryptic digestion, as previously described [14], [17]. Briefly, gliadin was separated from wheat flour by a 70% ethanol aqueous solution.…”

Section: Methodsmentioning

confidence: 99%

“…We described p10-mer, a decapeptide (sequence QQPQDAVQPF) [13] that prevents the activation of peripheral celiac lymphocytes by gliadin peptides [14] and promotes a shift from a Th1-type response toward a Th2-type response in celiac disease [15]. In the present study we evaluated "in vitro" the modulating effect of p10-mer on gliadin-triggered intestinal epithelial cell inflammation.…”

Section: Introductionmentioning

confidence: 99%

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Modulatory Effect of Gliadin Peptide 10-mer on Epithelial Intestinal CACO-2 Cell Inflammatory Response

et al. 2013

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Celiac Disease (CD) is a chronic inflammatory enteropathy, triggered in genetically susceptible individuals by dietary gluten. Gluten is able to elicit proliferation of specific T cells and secretion of inflammatory cytokines in the small intestine. In this study we investigated the possibility that p10-mer, a decapeptide from durum wheat (QQPQDAVQPF), which was previously shown to prevent the activation of celiac peripheral lymphocytes, may exert an inhibitory effect on peptic-tryptic digested gliadin (PT-Gly)-stimulated intestinal carcinoma CACO-2 cells. In these cells, incubated with PT-Gly or p31-43 α-gliadin derived peptide in the presence or in the absence of p10-mer, IRAK1 activation and NF-kB, ERK1/2 and p38 MAPK phosphorylation were measured by immunoblotting, Cyclooxigenase 2 (COX-2) activity by PGE-2 release assay, and production of cytokines in the cell supernatants by ELISA. Our results showed that pre-treatment of CACO-2 cells with p10-mer significantly inhibited IRAK1 activation and NF-kB, ERK1/2 and p38 MAPK phosphorylation, as well as COX-2 activity (i.e. PGE-2 release) and production of the IL-6 and IL-8 pro-inflammatory cytokines, induced by gliadin peptides. These findings demonstrate the inhibitory effect of the p10-mer peptide on inflammatory response in CACO-2 cells. The results of the present study show that this p10-mer peptide can modulate "in vitro" the inflammatory response induced by gliadin peptides, allowing to move towards new therapeutic strategies. Turning off the inflammatory response, may in fact represent a key target in the immunotherapy of celiac disease.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Modulatory Effect of Gliadin Peptide 10-mer on Epithelial Intestinal CACO-2 Cell Inflammatory Response

et al. 2013

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“…Inducing a switch from TH1/TH17 to TH2 has been proposed as a potential treatment for celiac disease [7]. Regulatory T cells (Tregs) also have a role in celiac disease, with recent studies showing increased numbers of circulating and mucosal CD4+Foxp3+ cells in individuals with active celiac disease, as compared to those on a gluten-free diet [8], [9].…”

Section: Introductionmentioning

confidence: 99%

Suppression of Inflammatory Immune Responses in Celiac Disease by Experimental Hookworm Infection

et al. 2011

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We present immunological data from two clinical trials where the effect of experimental human hookworm (Necator americanus) infection on the pathology of celiac disease was evaluated. We found that basal production of Interferon- (IFN-)γ and Interleukin- (IL-)17A from duodenal biopsy culture was suppressed in hookworm-infected participants compared to uninfected controls. Increased levels of CD4+CD25+Foxp3+ cells in the circulation and mucosa are associated with active celiac disease. We show that this accumulation also occurs during a short-term (1 week) oral gluten challenge, and that hookworm infection suppressed the increase of circulating CD4+CD25+Foxp3+ cells during this challenge period. When duodenal biopsies from hookworm-infected participants were restimulated with the immunodominant gliadin peptide QE65, robust production of IL-2, IFN-γ and IL-17A was detected, even prior to gluten challenge while participants were strictly adhering to a gluten-free diet. Intriguingly, IL-5 was produced only after hookworm infection in response to QE65. Thus we hypothesise that hookworm-induced TH2 and IL-10 cross-regulation of the TH1/TH17 inflammatory response may be responsible for the suppression of these responses during experimental hookworm infection.

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“…In addition, IL-13 gene therapy in rheumatoid arthritis synovium reduced inflammatory cytokines and prostaglandin E 2 [ 155 ]. Moreover, the effectiveness of current treatments for RA, such as anti-tumor necrosis factor and methotrexate therapy, may be due in part to inducing a TH2 shift [ 156 157 ], and inducing a TH2 shift has been proposed as a potential therapy for celiac disease [ 158 ], MS [ 159 ], kidney ischemia-reperfusion injury [ 160 ], and for prolongation of cardiac allograft viability [ 161 ].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of G-Protein βγ Signaling Decreases Levels of Messenger RNAs Encoding Proinflammatory Cytokines in T Cell Receptor-Stimulated CD4+ T Helper Cells

Hynes¹,

Yost²,

Hartle³

et al. 2015

Journal of Molecular Signaling

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Background: Inhibition of G-protein βγ (Gβγ) signaling was found previously to enhance T cell receptor (TCR)-stimulated increases in interleukin 2 (IL-2) mRNA in CD4+ T helper cells, suggesting that Gβγ might be a useful drug target for treating autoimmune diseases, as low dose IL-2 therapy can suppress autoimmune responses. Because IL-2 may counteract autoimmunity in part by shifting CD4+ T helper cells away from the Type 1 T helper cell (TH1) and TH17 subtypes towards the TH2 subtype, the purpose of this study was to determine if blocking Gβγ signaling affected the balance of TH1, TH17, and TH2 cytokine mRNAs produced by CD4+ T helper cells.Methods: Gallein, a small molecule inhibitor of Gβγ, and siRNA-mediated silencing of the G-protein β1 subunit (Gβ1) were used to test the effect of blocking Gβγ on mRNA levels of cytokines in primary human TCR-stimulated CD4+ T helper cells.Results: Gallein and Gβ1 siRNA decreased interferon-γ (IFN-γ) and IL-17A mRNA levels in TCR-stimulated CD4+ T cells grown under TH1-promoting conditions. Inhibiting Gβγ also decreased mRNA levels of STAT4, which plays a positive role in TH1 differentiation and IL-17A production. Moreover, mRNA levels of the STAT4-regulated TH1-associated proteins, IL-18 receptor β chain (IL-18Rβ), mitogen-activated protein kinase kinase kinase 8 (MAP3K8), lymphocyte activation gene 3 (LAG-3), natural killer cell group 7 sequence (NKG7), and oncostatin M (OSM) were also decreased upon Gβγ inhibition. Gallein also increased IL-4, IL-5, IL-9, and IL-13 mRNA levels in TCR-stimulated memory CD4+ T cells grown in TH2-promoting conditions.Conclusions: Inhibiting Gβγ to produce these shifts in cytokine mRNA production might be beneficial for patients with autoimmune diseases such as rheumatoid arthritis (RA), Crohn’s disease (CD), psoriasis, multiple sclerosis (MS), and Hashimoto’s thyroiditis (HT), in which both IFN-γ and IL-17A are elevated.

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A 10-residue peptide from durum wheat promotes a shift from a Th1-type response toward a Th2-type response in celiac disease

Abstract: In vitro, p10mer showed the ability to shift the pathogenic immune response of a CD patient from a Th1- to a Th2-type response.

Cited by 25 publications

References 40 publications

Modulatory Effect of Gliadin Peptide 10-mer on Epithelial Intestinal CACO-2 Cell Inflammatory Response

Modulatory Effect of Gliadin Peptide 10-mer on Epithelial Intestinal CACO-2 Cell Inflammatory Response

Suppression of Inflammatory Immune Responses in Celiac Disease by Experimental Hookworm Infection

Inhibition of G-Protein βγ Signaling Decreases Levels of Messenger RNAs Encoding Proinflammatory Cytokines in T Cell Receptor-Stimulated CD4+ T Helper Cells

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