Abstract
Celiac disease (CD) is an enteropathy triggered by gluten and mediated by CD4+ T cells. A complete understanding of CD immunopathogenesis has been hindered due to the lack of adequate in vivo models. Here, we explored the effect of the inhibition of COX by indomethacin in wheat gliadin-sensitized transgenic mice expressing the HLA-DQ8 heterodimer, a molecule associated with CD. Treated mice showed a gliadin-specific immune response with a significant reduction of villus height, not linked to crypt hyperplasia and to expansion of intraepithelial T cells. Notably, treated mice showed increased numbers of CD25+ and apoptotic cells in the lamina propria, whereas high basal levels of IFN-gamma secretion, along with a reduced gliadin-specific IL-2 expression were detected in MLN. Biochemical assessment of the lesion revealed increased mRNA of Lamb3 and Adamts2, encoding for ECM proteins, and enhanced activities of metalloproteinases MMP1, 2 and 7. We conclude that an intestinal sensitivity to gliadin, in connection with COX inhibition, caused a decreased villus height in DQ8 tg mice. The lesion was induced by a deregulated mucosal cell immunity to gliadin, thus triggering activation of a specific ECM protein pathway responsible for lamina propria remodeling.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ADAM Proteins / genetics
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ADAMTS Proteins
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ADAMTS4 Protein
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Animals
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Apoptosis
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CD3 Complex / metabolism
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Celiac Disease / genetics
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Celiac Disease / immunology*
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Celiac Disease / metabolism
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Cell Adhesion Molecules / genetics
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Cyclooxygenase Inhibitors / pharmacology
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Forkhead Transcription Factors / metabolism
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Gliadin / immunology*
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HLA-DQ Antigens / genetics
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HLA-DQ Antigens / immunology*
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Humans
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Immunohistochemistry
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Indomethacin / pharmacology
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Interferon-gamma / metabolism
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Interleukin-2 / metabolism
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Interleukin-2 Receptor alpha Subunit / metabolism
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Intestinal Mucosa / immunology*
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Intestinal Mucosa / metabolism
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Intestinal Mucosa / pathology
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Kalinin
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Matrix Metalloproteinase 13 / metabolism
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Matrix Metalloproteinase 2 / metabolism
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Matrix Metalloproteinase 7 / metabolism
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Mice
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Mice, Transgenic
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Procollagen N-Endopeptidase / genetics
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Prostaglandin-Endoperoxide Synthases / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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T-Lymphocytes / pathology
Substances
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CD3 Complex
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Cell Adhesion Molecules
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Cyclooxygenase Inhibitors
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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HLA-DQ Antigens
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HLA-DQ8 antigen
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Interleukin-2
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Interleukin-2 Receptor alpha Subunit
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Interferon-gamma
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Gliadin
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Prostaglandin-Endoperoxide Synthases
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ADAM Proteins
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ADAMTS Proteins
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Matrix Metalloproteinase 13
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Mmp13 protein, mouse
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ADAMTS2 protein, human
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Adamts2 protein, mouse
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Procollagen N-Endopeptidase
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Matrix Metalloproteinase 7
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MMP2 protein, human
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Matrix Metalloproteinase 2
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ADAMTS4 Protein
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Indomethacin