Smad2 and Smad3 Inversely Regulate TGF-β Autoinduction in Clostridium butyricum-Activated Dendritic Cells

Colonizationwith a mixture of Clostridium species has been shown to induce accumulation of induced regulatory T (iTreg) cells in the colon. Transforming growth factor-beta (TGF-beta) is an essential factor for iTreg cell induction; however, the relationship between Clostridium species and TGF-beta remains to be clarified. Here we demonstrated that a gram-positive probiotic bacterial strain, Clostridium butyricum(C. butyricum), promoted iTreg cell generation in the intestine through induction of TGF-beta 1 from lamina propria dendritic cells (LPDCs). C. butyricum-mediated TGF-beta 1 induction was mainly Toll-like receptor 2 (TLR2) dependent, and the ERK-AP-1 kinase pathway played an important role. In addition, the autocrine TGF-beta-Smad3 transcription factor signal was necessary for robust TGF-beta expression in DCs, whereas Smad2 negatively regulated TGF-beta expression. Smad2-deficient DCs expressed higher concentrations of TGF-beta and were tolerogenic for colitismodels. This study reveals a novel mechanism of TGF-beta induction by Clostridia through a cooperation between TLR2-AP-1 and TGF-beta-Smad signaling pathways.