TITLE

Blockade of transforming growth factor β upregulates 1-box transcription factor 1-bet, and increases I helper cell type 1 cytokine and matrix metalloproteinase-3 production in the human gut mucosa

AUTHOR(S)
Di Sabatino, A.; Pickard, K. M.; Rampton, D.; Kruidenier, L.; Rovedatti, L.; Leakey, N. A. B.; Corazza, G. A.; Monteleone, G.; Macdonald, T. T.
PUB. DATE
May 2008
SOURCE
Gut;May2008, Vol. 57 Issue 5, p605
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
BACKGROUND AND AIMS: The role of transforming growth factor beta (TGFβ) in inhibiting T cell function in the normal gut has been studied in animal models. However, the impact of TGFβ inhibition on T cells in the normal human gut remains poorly understood. The effect of TGFβ blockade in normal intestinal biopsies grown ex vivo and lamina propria mononuclear cells (LPMCs) on T-bet, a T-box transcription factor required for T helper cell type (Th)1 differentiation, interferon γ (IFN γ) production, T cell apoptosis and matrix metalloproteinase (MMP)-3 production has therefore been tested. METHODS: TGFβ transcripts were determined by quantitative reverse transcription-PCR in laser-captured gut epithelium and lamina propria. Biopsies and LPMCs were cultured with anti-TGFβ neutralising antibody. After 24 h culture, T-bet was determined by immunoblotting, and T cell apoptosis was assessed by flow cytometry. IFN γ, tumour necrosis factor α (TNFα), interleukin (IL) 2, IL6, IL8, IL10, IL12p70 and IL17 were measured by ELISA. MMP-3 and tissue inhibitor of matrix metalloproteinase (TIMP)-1 were assessed by immunoblotting. RESULTS: A higher number of TGFβ transcripts was found in the lamina propria than in the epithelium in normal gut. T-bet expression was significantly higher in biopsies and LPMCs cultured with anti-TGFβ antibody than in those cultured with control antibody. TGFβ blockade downregulated T cell apoptosis, and induced a significant increase in IFN γ, TNFα, IL2, IL6, IL8 and IL17 production. A higher expression of MMP-3, but not TIMP-1, was observed in the tissue and supernatant of biopsies treated with anti-TGFβ antibody. CONCLUSIONS: The findings support a crucial role for TGFβ in dampening T cell-mediated tissue-damaging responses in the human gut.
ACCESSION #
31931730

 

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