Document Detail


Transglutaminase 2 expression is enhanced synergistically by interferon-γ and tumour necrosis factor-α in human small intestine.
MedLine Citation:
PMID:  22385244     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Transglutaminase 2 (TG2) is expressed ubiquitously, has multiple physiological functions and has also been associated with inflammatory diseases, neurodegenerative disorders, autoimmunity and cancer. In particular, TG2 is expressed in small intestine mucosa where it is up-regulated in active coeliac disease (CD). The aim of this work was to investigate the induction of TG2 expression by proinflammatory cytokines [interleukin (IL)-1, IL-6, tumour necrosis factor (TNF)-α, interferon (IFN)-γ and IL-15] and the signalling pathways involved, in human epithelial and monocytic cells and in intestinal tissue from controls and untreated CD patients. Here we report that IFN-γ was the most potent inducer of TG2 expression in the small intestinal mucosa and in four [Caco-2, HT-29, Calu-6 and human acute monocytic leukaemia cell line (THP-1)] of five cell lines tested. The combination of TNF-α and IFN-γ produced a strong synergistic effect. The use of selective inhibitors of signalling pathways revealed that induction of TG2 by IFN-γ was mediated by phosphoinositide 3-kinase (PI3K), while c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) were required for TNF-α activation. Quantitative polymerase chain reaction (PCR), flow cytometry and Western blot analysis showed that TG2 expression was blocked completely when stimulation by either TNF-α or IFN-γ was performed in the presence of nuclear factor (NF)-κB inhibitors (sulphasalazine and BAY-117082). TG2 was up-regulated substantially by TNF-α and IFN-γ in intestinal mucosa in untreated CD compared with controls. This study shows that IFN-γ, a dominant cytokine in intestinal mucosa in active CD, is the most potent inducer of TG2, and synergism with TNF-α may contribute to exacerbate the pathogenic mechanism of CD. Selective inhibition of signalling pathways may be of therapeutic benefit.
Authors:
M Bayardo; F Punzi; C Bondar; N Chopita; F Chirdo
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Clinical and experimental immunology     Volume:  168     ISSN:  1365-2249     ISO Abbreviation:  Clin. Exp. Immunol.     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-03-05     Completed Date:  2012-05-04     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  0057202     Medline TA:  Clin Exp Immunol     Country:  England    
Other Details:
Languages:  eng     Pagination:  95-104     Citation Subset:  IM    
Copyright Information:
© 2011 The Authors. Clinical and Experimental Immunology © 2011 British Society for Immunology.
Affiliation:
Laboratorio de Investigación en el Sistema Inmune, Departamento de Ciencias Biológicas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata Servicio de Gastroenterología, Hospital Interzonal de Agudos José de San Martin, La Plata, Argentina.
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MeSH Terms
Descriptor/Qualifier:
Celiac Disease / immunology,  metabolism*
Cell Line
Epithelial Cells / metabolism
GTP-Binding Proteins / biosynthesis*
Humans
Interferon-gamma / metabolism*
Interleukin-1 / metabolism
Interleukin-15 / metabolism
Interleukin-6 / metabolism
Intestinal Mucosa / immunology,  metabolism*
Intestine, Small / immunology,  metabolism
JNK Mitogen-Activated Protein Kinases / metabolism
Leukocytes, Mononuclear / metabolism
NF-kappa B / antagonists & inhibitors
Nitriles / pharmacology
Phosphatidylinositol 3-Kinases / metabolism
Signal Transduction
Sulfasalazine / pharmacology
Sulfones / pharmacology
Transglutaminases / biosynthesis*
Tumor Necrosis Factor-alpha / metabolism*
p38 Mitogen-Activated Protein Kinases / metabolism
Chemical
Reg. No./Substance:
0/3-(4-methylphenylsulfonyl)-2-propenenitrile; 0/Interleukin-1; 0/Interleukin-15; 0/Interleukin-6; 0/NF-kappa B; 0/Nitriles; 0/Sulfones; 0/Tumor Necrosis Factor-alpha; 599-79-1/Sulfasalazine; 82115-62-6/Interferon-gamma; EC 2.3.2.-/transglutaminase 2; EC 2.3.2.13/Transglutaminases; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.11.24/JNK Mitogen-Activated Protein Kinases; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases; EC 3.6.1.-/GTP-Binding Proteins
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