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.

• MeSH
• adaptorové proteiny vezikulární transportní genetika   imunologie   MeSH
• celiakie MeSH
• dospělí MeSH
• gliadin chemie   imunologie   MeSH
• inflamasomy účinky léků   genetika   imunologie   MeSH
• interleukin-1beta genetika   imunologie   MeSH
• leukocyty mononukleární účinky léků   imunologie   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mitogenem aktivované proteinkinasy genetika   imunologie   MeSH
• myši knockoutované MeSH
• myši MeSH
• pepsin A MeSH
• peptidové fragmenty farmakologie   MeSH
• primární buněčná kultura MeSH
• protein MyD88 genetika   imunologie   MeSH
• regulace genové exprese účinky léků   imunologie   MeSH
• signální transdukce účinky léků   genetika   imunologie   MeSH
• toll-like receptor 2 genetika   imunologie   MeSH
• toll-like receptor 4 genetika   imunologie   MeSH
• transportní proteiny genetika   imunologie   MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH