title: 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.
abstract: Celiac disease (CD) is a gluten-responsive, chronic inflammatory enteropathy. IL-1 cytokine family members IL-1β and IL-18 have been associated with the inflammatory conditions in CD patients. However, the mechanisms of IL-1 molecule activation in CD have not yet been elucidated. We show in this study that peripheral blood mononuclear cells (PBMC) and monocytes from celiac patients responded to pepsin digest of wheat gliadin fraction (PDWGF) by a robust secretion of IL-1β and IL-1α and a slightly elevated production of IL-18. The analysis of the upstream mechanisms underlying PDWGF-induced IL-1β production in celiac PBMC show that PDWGF-induced de novo pro-IL-1β synthesis, followed by a caspase-1 dependent processing and the secretion of mature IL-1β. This was promoted by K+ efflux and oxidative stress, and was independent of P2X7 receptor signaling. The PDWGF-induced IL-1β release was dependent on Nod-like receptor family containing pyrin domain 3 (NLRP3) and apoptosis-associated speck like protein (ASC) as shown by stimulation of bone marrow derived dendritic cells (BMDC) from NLRP3(-/-) and ASC(-/-) knockout mice. Moreover, treatment of human PBMC as well as MyD88(-/-) and Toll-interleukin-1 receptor domain-containing adaptor-inducing interferon-β (TRIF)(-/-) BMDC illustrated that prior to the activation of caspase-1, the PDWGF-triggered signal constitutes the activation of the MyD88/TRIF/MAPK/NF-κB pathway. Moreover, our results indicate that the combined action of TLR2 and TLR4 may be required for optimal induction of IL-1β in response to PDWGF. Thus, innate immune pathways, such as TLR2/4/MyD88/TRIF/MAPK/NF-κB and an NLRP3 inflammasome activation are involved in wheat proteins signaling and may play an important role in the pathogenesis of CD.
authors: Institute of Microbiology, Department of Immunology, Academy of Sciences of the Czech Republic, Prague, Czech Republic. lenicka@biomed.cas.cz
authors: Lenka
authors: L
authors: Palová-Jelínková
authors: Klára
authors: K
authors: Dáňová
authors: Hana
authors: H
authors: Drašarová
authors: Miloš
authors: M
authors: Dvořák
authors: David P
authors: DP
authors: Funda
authors: Petra
authors: P
authors: Fundová
authors: Anna
authors: A
authors: Kotrbová-Kozak
authors: Marie
authors: M
authors: Černá
authors: Jana
authors: J
authors: Kamanová
authors: Stefan F
authors: SF
authors: Martin
authors: Marina
authors: M
authors: Freudenberg
authors: Ludmila
authors: L
authors: Tučková
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000276:immunology; D000328:Adult; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D002446:Celiac Disease; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D005903:Gliadin / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D058847:Inflammasomes / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010434:Pepsin A; D010446:Peptide Fragments / Q000494:pharmacology*; D061251:Primary Cell Culture; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D010446:Peptide Fragments; C470409:TICAM1 protein, human; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D005903:Gliadin; D020928:Mitogen-Activated Protein Kinases; D010434:Pepsin A
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