Reciprocal regulation of TGF-β and reactive oxygen species: A perverse cycle for fibrosis

Transforming growth factor beta (TGF-beta) is the most potent pro-fibrogenic cytokine and its expression is increased in almost all of fibrotic diseases. Although signaling through Smad pathway is believed to play a central role in TGF-beta's fibrogenesis, emerging evidence indicates that reactive oxygen species (ROS) modulate TGF-beta's signaling through different pathways including Smad pathway. TGF-beta 1 increases ROS production and suppresses antioxidant enzymes, leading to a redox imbalance. ROS, in turn, induce/activate TGF-beta 1 and mediate many of TGF-beta's fibrogenic effects, forming a vicious cycle (see graphic flow chart on the right). Here, we review the current knowledge on the feed-forward mechanisms between TGF-beta 1 and ROS in the development of fibrosis. Therapeutics targeting TGF-beta-induced and ROS-dependent cellular signaling represents a novel approach in the treatment of fibrotic disorders. (C) 2015 The Authors. Published by Elsevier B.V.