Gliadin fragments promote migration of dendritic cells.
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.
Chladkova
Barbara
B
Laboratory of Specific Cellular Immunity, Institute of Microbiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Kamanova
Jana
J
Palova-Jelinkova
Lenka
L
Cinova
Jana
J
Sebo
Peter
P
Tuckova
Ludmila
L
D054415:Chemokine CCL19 / Q000494:pharmacology; D054421:Chemokine CCL21 / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology; D015232:Dinoprostone / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D005903:Gliadin / Q000494:pharmacology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008954:Models, Biological; D010446:Peptide Fragments / Q000494:pharmacology*; D054400:Receptors, CCR7 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C515370:CCR7 protein, human; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D010446:Peptide Fragments; D054400:Receptors, CCR7; D005903:Gliadin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone
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