In genetically predisposed individuals, ingestion of wheat gliadin provokes a T-cell-mediated enteropathy, celiac disease. Gliadin fragments were previously reported to induce phenotypic maturation and Th1 cytokine production by human dendritic cells (DCs) and to boost their capacity to stimulate allogeneic T cells. Here, we monitor the effects of gliadin on migratory capacities of DCs. Using transwell assays, we show that gliadin peptic digest stimulates migration of human DCs and their chemotactic responsiveness to the lymph node-homing chemokines CCL19 and CCL21. The gliadin-induced migration is accompanied by extensive alterations of the cytoskeletal organization, with dissolution of adhesion structures, podosomes, as well as up-regulation of the CC chemokine receptor (CCR) 7 on cell surface and induction of cyclooxygenase (COX)-2 enzyme that mediates prostaglandin E2 (PGE₂) production. Blocking experiments confirmed that gliadin-induced migration is independent of the TLR4 signalling. Moreover, we showed that the α-gliadin-derived 31-43 peptide is an active migration-inducing component of the digest. The migration promoted by gliadin fragments or the 31-43 peptide required activation of p38 mitogen-activated protein kinase (MAPK). As revealed using p38 MAPK inhibitor SB203580, this was responsible for DC cytoskeletal transition, CCR7 up-regulation and PGE₂ production in particular. Taken together, this study provides a new insight into pathogenic features of gliadin fragments by demonstrating their ability to promote DC migration, which is a prerequisite for efficient priming of naive T cells, contributing to celiac disease pathology.

Laboratory of Specific Cellular Immunity Institute of Microbiology Academy of Sciences of the Czech Republic Prague Czech Republic

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Sollid LM, Markussen G, Ek J, et al. Evidence for a primary association of celiac disease to a particular HLA-DQ alpha/beta heterodimer. J Exp Med. 1989;169:345–50. PubMed PMC

Di Sabatino A, Corazza GR. Coeliac disease. Lancet. 2009;373:1480–93. PubMed

Spurkland A, Sollid LM, Polanco I, et al. HLA-DR and -DQ genotypes of celiac disease patients serologically typed to be non-DR3 or non-DR5/7. Hum Immunol. 1992;35:188–92. PubMed

Molberg O, McAdam SN, Korner R, et al. Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nat Med. 1998;4:713–7. PubMed

Schuppan D. Current concepts of celiac disease pathogenesis. Gastroenterology. 2000;119:234–42. PubMed

Villanacci V, Not T, Sblattero D, et al. Mucosal tissue transglutaminase expression in celiac disease. J Cell Mol Med. 2009;13:334–40. PubMed PMC

Shan L, Molberg O, Parrot I, et al. Structural basis for gluten intolerance in celiac sprue. Science. 2002;297:2275–9. PubMed

Nilsen EM, Jahnsen FL, Lundin KE, et al. Gluten induces an intestinal cytokine response strongly dominated by interferon gamma in patients with celiac disease. Gastroenterology. 1998;115:551–63. PubMed

Sollid LM. Intraepithelial lymphocytes in celiac disease: license to kill revealed. Immunity. 2004;21:303–4. PubMed

Hue S, Mention JJ, Monteiro RC, et al. A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease. Immunity. 2004;21:367–77. PubMed

Meresse B, Chen Z, Ciszewski C, et al. Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease. Immunity. 2004;21:357–66. PubMed

Tuckova L, Novotna J, Novak P, et al. Activation of macrophages by gliadin fragments: isolation and characterization of active peptide. J Leukoc Biol. 2002;71:625–31. PubMed

Thomas KE, Sapone A, Fasano A, et al. Gliadin stimulation of murine macrophage inflammatory gene expression and intestinal permeability are MyD88-dependent: role of the innate immune response in Celiac disease. J Immunol. 2006;176:2512–21. PubMed

Cinova J, Palova-Jelinkova L, Smythies LE, et al. Gliadin peptides activate blood monocytes from patients with celiac disease. J Clin Immunol. 2007;27:201–9. PubMed

Nikulina M, Habich C, Flohe SB, et al. Wheat gluten causes dendritic cell maturation and chemokine secretion. J Immunol. 2004;173:1925–33. PubMed

Palova-Jelinkova L, Rozkova D, Pecharova B, et al. Gliadin fragments induce phenotypic and functional maturation of human dendritic cells. J Immunol. 2005;175:7038–45. PubMed

Rakhimova M, Esslinger B, Schulze-Krebs A, et al. In vitro differentiation of human monocytes into dendritic cells by peptic-tryptic digest of gliadin is independent of genetic predisposition and the presence of celiac disease. J Clin Immunol. 2009;29:29–37. PubMed

Maiuri L, Ciacci C, Ricciardelli I, et al. Association between innate response to gliadin and activation of pathogenic T cells in coeliac disease. Lancet. 2003;362:30–7. PubMed

Jabri B, Sollid LM. Tissue-mediated control of immunopathology in coeliac disease. Nat Rev Immunol. 2009;9:858–70. PubMed

Brandtzaeg P. The changing immunological paradigm in coeliac disease. Immunol Lett. 2006;105:127–39. PubMed

Banchereau J, Briere F, Caux C, et al. Immunobiology of dendritic cells. Annu Rev Immunol. 2000;18:767–811. PubMed

Alvarez D, Vollmann EH, von Andrian UH. Mechanisms and consequences of dendritic cell migration. Immunity. 2008;29:325–42. PubMed PMC

Randolph GJ, Angeli V, Swartz MA. Dendritic-cell trafficking to lymph nodes through lymphatic vessels. Nat Rev Immunol. 2005;5:617–28. PubMed

van Helden SF, Krooshoop DJ, Broers KC, et al. A critical role for prostaglandin E2 in podosome dissolution and induction of high-speed migration during dendritic cell maturation. J Immunol. 2006;177:1567–74. PubMed

De Vries IJ, Krooshoop DJ, Scharenborg NM, et al. Effective migration of antigen-pulsed dendritic cells to lymph nodes in melanoma patients is determined by their maturation state. Cancer Res. 2003;63:12–7. PubMed

Burns S, Thrasher AJ, Blundell MP, et al. Configuration of human dendritic cell cytoskeleton by Rho GTPases, the WAS protein, and differentiation. Blood. 2001;98:1142–9. PubMed

Burns S, Hardy SJ, Buddle J, et al. Maturation of DC is associated with changes in motile characteristics and adherence. Cell Motil Cytoskeleton. 2004;57:118–32. PubMed

Linder S, Aepfelbacher M. Podosomes: adhesion hot-spots of invasive cells. Trends Cell Biol. 2003;13:376–85. PubMed

Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392:245–52. PubMed

Benvenuti F, Hugues S, Walmsley M, et al. Requirement of Rac1 and Rac2 expression by mature dendritic cells for T cell priming. Science. 2004;305:1150–3. PubMed

Martin-Fontecha A, Sebastiani S, Hopken UE, et al. Regulation of dendritic cell migration to the draining lymph node: impact on T lymphocyte traffic and priming. J Exp Med. 2003;198:615–21. PubMed PMC

Dieu MC, Vanbervliet B, Vicari A, et al. Selective recruitment of immature and mature dendritic cells by distinct chemokines expressed in different anatomic sites. J Exp Med. 1998;188:373–86. PubMed PMC

Sallusto F, Schaerli P, Loetscher P, et al. Rapid and coordinated switch in chemokine receptor expression during dendritic cell maturation. Eur J Immunol. 1998;28:2760–9. PubMed

Sozzani S, Allavena P, D’Amico G, et al. Differential regulation of chemokine receptors during dendritic cell maturation: a model for their trafficking properties. J Immunol. 1998;161:1083–6. PubMed

Robbiani DF, Finch RA, Jager D, et al. The leukotriene C(4) transporter MRP1 regulates CCL19 (MIP-3beta, ELC)-dependent mobilization of dendritic cells to lymph nodes. Cell. 2000;103:757–68. PubMed

Scandella E, Men Y, Gillessen S, et al. Prostaglandin E2 is a key factor for CCR7 surface expression and migration of monocyte-derived dendritic cells. Blood. 2002;100:1354–61. PubMed

Kabashima K, Sakata D, Nagamachi M, et al. Prostaglandin E2-EP4 signaling initiates skin immune responses by promoting migration and maturation of Langerhans cells. Nat Med. 2003;9:744–9. PubMed

Scandella E, Men Y, Legler DF, et al. CCL19/CCL21-triggered signal transduction and migration of dendritic cells requires prostaglandin E2. Blood. 2004;103:1595–601. PubMed

Legler DF, Krause P, Scandella E, et al. Prostaglandin E2 is generally required for human dendritic cell migration and exerts its effect via EP2 and EP4 receptors. J Immunol. 2006;176:966–73. PubMed

Teloni R, Giannoni F, Rossi P, et al. Interleukin-4 inhibits cyclo-oxygenase-2 expression and prostaglandin E production by human mature dendritic cells. Immunology. 2007;120:83–9. PubMed PMC

Fogel-Petrovic M, Long JA, Knight DA, et al. Activated human dendritic cells express inducible cyclo-oxygenase and synthesize prostaglandin E2 but not prostaglandin D2. Immunol Cell Biol. 2004;82:47–54. PubMed

Steinman RM, Hawiger D, Nussenzweig MC. Tolerogenic dendritic cells. Annu Rev Immunol. 2003;21:685–711. PubMed

Cerovic V, McDonald V, Nassar MA, et al. New insights into the roles of dendritic cells in intestinal immunity and tolerance. Int Rev Cell Mol Biol. 2009;272:33–105. PubMed

Harris KM, Fasano A, Mann DL. Cutting edge: IL-1 controls the IL-23 response induced by gliadin, the etiologic agent in celiac disease. J Immunol. 2008;181:4457–60. PubMed

Dubois PCA, Trynka G, Franke L, et al. Multiple common variants for celiac disease influencing immune gene expression. Nat Genet. 2010 http://dx.doi.org/10.1038/ng.543. PubMed DOI PMC

Hunt KA, Zhernakova A, Turner G, et al. Newly identified genetic risk variants for celiac disease related to the immune response. Nat Genet. 2008;40:395–402. PubMed PMC

van Heel DA, Franke L, Hunt KA, et al. A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21. Nat Genet. 2007;39:827–9. PubMed PMC

Zhernakova A, van Diemen CC, Wijmenga C. Detecting shared pathogenesis from the shared genetics of immune-related diseases. Nat Rev Genet. 2009;10:43–55. PubMed

Monsuur AJ, de Bakker PI, Alizadeh BZ, et al. Myosin IXB variant increases the risk of celiac disease and points toward a primary intestinal barrier defect. Nat Genet. 2005;37:1341–4. PubMed

Hunt KA, Monsuur AJ, McArdle WL, et al. Lack of association of MYO9B genetic variants with coeliac disease in a British cohort. Gut. 2006;55:969–72. PubMed PMC

De Palma G, Cinova J, Stepankova R, et al. Pivotal advance: bifidobacteria and gram-negative bacteria differentially influence immune responses in the proinflammatory milieu of celiac disease. J Leukoc Biol. 2010;87:765–78. PubMed

Gianfrani C, Levings MK, Sartirana C, et al. Gliadin-specific type 1 regulatory T cells from the intestinal mucosa of treated celiac patients inhibit pathogenic T cells. J Immunol. 2006;177:4178–86. PubMed

Granzotto M, dal Bo S, Quaglia S, et al. Regulatory T-cell function is impaired in celiac disease. Dig Dis Sci. 2009;54:1513–9. PubMed

Bouchon A, Hernandez-Munain C, Cella M, et al. A DAP12-mediated pathway regulates expression of CC chemokine receptor 7 and maturation of human dendritic cells. J Exp Med. 2001;194:1111–22. PubMed PMC

De Vincenzi M, Dessi MR, Giovannini C, et al. Agglutinating activity of wheat gliadin peptide fractions in coeliac disease. Toxicology. 1995;96:29–35. PubMed

De Vincenzi M, Stammati A, Luchetti R, et al. Structural specificities and significance for coeliac disease of wheat gliadin peptides able to agglutinate or to prevent agglutination of K562(S) cells. Toxicology. 1998;127:97–106. PubMed

Barone MV, Gimigliano A, Castoria G, et al. Growth factor-like activity of gliadin, an alimentary protein: implications for coeliac disease. Gut. 2007;56:480–8. PubMed PMC

Vilasi S, Sirangelo I, Irace G, et al. Interaction of ‘toxic’ and ‘immunogenic’ A-gliadin peptides with a membrane-mimetic environment. J Mol Recognit. 2010;23:322–8. PubMed

Lammers KM, Lu R, Brownley J, et al. Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. Gastroenterology. 2008;135:194–204. PubMed PMC

Pore-formation by adenylate cyclase toxoid activates dendritic cells to prime CD8+ and CD4+ T cells

Pepsin digest of wheat gliadin fraction increases production of IL-1β via TLR4/MyD88/TRIF/MAPK/NF-κB signaling pathway and an NLRP3 inflammasome activation