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Blockade of transforming growth factor-β up-regulates T-box transcription factor T-bet, and increases T helper cell type 1 cytokine and matrix metalloproteinase-3 production in the human gut mucosa
  1. Antonio Di Sabatino (a.disabatino{at}smatteo.pv.it)
  1. Centre for Infectious Disease, ICMS, Barts and the London, United Kingdom
    1. Karen M Pickard (a.disabatino{at}smatteo.pv.it)
    1. Division of Infection, Inflammation and Repair, University of Southampton, United Kingdom
      1. David Rampton (a.disabatino{at}smatteo.pv.it)
      1. Centre for Gastroenterology, ICMS, Barts and the London, United Kingdom
        1. Laurens Kruidenier
        1. GI and Neurosciences CEDD, GlaxoSmithKline, United Kingdom
          1. Laura Rovedatti
          1. Centre for Infectious Disease, ICMS, Barts and the London, United Kingdom
            1. Nicholas AB Leakey
            1. Centre for Infectious Disease, ICMS, Barts and the London, United Kingdom
              1. Gino R Corazza
              1. Policlinico S. Matteo, University of Pavia, Italy
                1. Giovanni Monteleone
                1. Dipartimento di Medicina Interna, Univerità di Tor Vergata, Rome, Italy
                  1. Thomas T MacDonald
                  1. Centre for Infectious Disease, ICMS, Barts and the London, United Kingdom

                    Abstract

                    Background & Aims: The role of transforming growth factor (TGF)-β in inhibiting T cell function in the normal gut has been studied in animal models. However, the impact of TGF-β inhibition on T cells in the normal human gut remains poorly understood. We have therefore tested the effect of TGF-β 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 (IFN)-γ production, T-cell apoptosis, and matrix metalloproteinase (MMP)-3 production.

                    Methods: TGF-β transcripts were determined by qRT-PCR in laser-captured gut epithelium and lamina propria. Biopsies and LPMCs were cultured with anti-TGF-β neutralizing antibody. After 24-h culture, T-bet was determined by immunoblotting and T-cell apoptosis was assessed by flow cytometry. IFN-γ, tumor necrosis factor-α, interleukin (IL)-2, IL-8, IL-10, IL-12p70 and IL-17 were measured by ELISA. MMP-3 and tissue inhibitor of matrix metalloproteinase (TIMP)-1 were assessed by immunoblotting.

                    Results: A higher number of TGF-β transcripts was found in the lamina propria than epithelium in normal gut. T-bet expression was significantly higher in biopsies and LPMCs cultured with anti-TGF-β antibody than with control antibody. TGF-β blockade down-regulated T-cell apoptosis, and induced a significant increase in IFN-γ, TNF-α, IL-2, IL-6, IL-8, and IL-17 production. A higher expression of MMP-3, but not TIMP-1, was observed in the tissue and supernatant of biopsies treated with anti-TGF-β antibody.

                    Conclusions: Our findings support a crucial role for TGF-β in dampening T cell-mediated tissue-damaging responses in the human gut.

                    • MMP-3
                    • T-bet
                    • TGF-beta
                    • Th1 cytokine
                    • apoptosis

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