Blockade of transforming growth factor β upregulates T-box transcription factor T-bet, and increases T helper cell type 1 cytokine and matrix metalloproteinase-3 production in the human gut mucosa. Issue 5 (4th January 2008)

• Record Type: Journal Article
• Authors: Di Sabatino, A; Pickard, K M; Rampton, D; Kruidenier, L; Rovedatti, L; Leakey, N A B; Corazza, G R; Monteleone, G; MacDonald, T T
• Is Part Of: Gut. Volume 57:Issue 5(2008)
• Page Start: 605
• Page End: 612
• Publication Date: 2008-01-04
• Subjects: Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gut.2007.130922
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Background and Aims: The role of transforming growth factor β (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 (IFNγ) 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. IFNγ, 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 IFNγ, 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.