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Gliadin Stimulation of Murine Macrophage Inflammatory Gene Expression and Intestinal Permeability Are MyD88-Dependent: Role of the Innate Immune Response in Celiac Disease

Karen E. Thomas, Anna Sapone, Alessio Fasano and Stefanie N. Vogel
J Immunol February 15, 2006, 176 (4) 2512-2521; DOI: https://doi.org/10.4049/jimmunol.176.4.2512
Karen E. Thomas
*Department of Microbiology and Immunology,
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Anna Sapone
†Center for Celiac Research, Department of Pediatrics, and
‡Mucosal Biology Research Center, University of Maryland School of Medicine, Baltimore, MD 21201
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Alessio Fasano
†Center for Celiac Research, Department of Pediatrics, and
‡Mucosal Biology Research Center, University of Maryland School of Medicine, Baltimore, MD 21201
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Stefanie N. Vogel
*Department of Microbiology and Immunology,
‡Mucosal Biology Research Center, University of Maryland School of Medicine, Baltimore, MD 21201
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Abstract

Recent studies have demonstrated the importance of TLR signaling in intestinal homeostasis. Celiac disease (CD) is an autoimmune enteropathy triggered in susceptible individuals by the ingestion of gliadin-containing grains. In this study, we sought to test the hypothesis that gliadin initiates this response by stimulating the innate immune response to increase intestinal permeability and by up-regulating macrophage proinflammatory gene expression and cytokine production. To this end, intestinal permeability and the release of zonulin (an endogenous mediator of gut permeability) in vitro, as well as proinflammatory gene expression and cytokine release by primary murine macrophage cultures, were measured. Gliadin and its peptide derivatives, 33-mer and p31-43, were found to be potent inducers of both a zonulin-dependent increase in intestinal permeability and macrophage proinflammatory gene expression and cytokine secretion. Gliadin-induced zonulin release, increased intestinal permeability, and cytokine production were dependent on myeloid differentiation factor 88 (MyD88), a key adapter molecule in the TLR/IL-1R signaling pathways, but were neither TLR2- nor TLR4-dependent. Our data support the following model for the innate immune response to gliadin in the initiation of CD. Gliadin interaction with the intestinal epithelium increases intestinal permeability through the MyD88-dependent release of zonulin that, in turn, enables paracellular translocation of gliadin and its subsequent interaction with macrophages within the intestinal submucosa. There, the interaction of gliadin with macrophages elicits a MyD88-dependent proinflammatory cytokine milieu that facilitates the interaction of T cells with APCs, leading ultimately to the Ag-specific adaptive immune response seen in patients with CD.

  • Received May 24, 2005.
  • Accepted November 16, 2005.
  • Copyright © 2006 by The American Association of Immunologists
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The Journal of Immunology: 176 (4)
The Journal of Immunology
Vol. 176, Issue 4
15 Feb 2006
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Gliadin Stimulation of Murine Macrophage Inflammatory Gene Expression and Intestinal Permeability Are MyD88-Dependent: Role of the Innate Immune Response in Celiac Disease
Karen E. Thomas, Anna Sapone, Alessio Fasano, Stefanie N. Vogel
The Journal of Immunology February 15, 2006, 176 (4) 2512-2521; DOI: 10.4049/jimmunol.176.4.2512

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Gliadin Stimulation of Murine Macrophage Inflammatory Gene Expression and Intestinal Permeability Are MyD88-Dependent: Role of the Innate Immune Response in Celiac Disease
Karen E. Thomas, Anna Sapone, Alessio Fasano, Stefanie N. Vogel
The Journal of Immunology February 15, 2006, 176 (4) 2512-2521; DOI: 10.4049/jimmunol.176.4.2512
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