Hydrogen Peroxide Is a Novel Inducer of Connective Tissue Growth Factor

Abstract

Connective tissue growth factor (CTGF) has recently been described as a fibrogenic factor and is greatly induced by various extracellular stimuli, such as transforming growth factor-beta (TGF-β), dexamethasone, and serotonin. CTGF induces collagen type I and fibronectin, and the deposition of such molecules leads to fibrotic disease in many tissues. Intracellular reactive oxygen species (ROS) are generated by extracellular stress conditions and are produced as by-products of cellular metabolism. Imbalanced cellular redox status is a potent pathogenic factor that leads to various degenerative diseases, including tissue fibrosis. Since CTGF is believed to play a crucial role in fibrotic disease formation in many tissues, we examined the role of ROS in CTGF gene expression in human lens epithelial cell line B3. The results showed that CTGF was induced by reactive oxygen species such as hydrogen peroxide and hydroxyl radicals. Next, we examined whether CTGF induction by ROS is via newly synthesized TGF-β. The results showed that ROS directly induced CTGF mRNA not via the increased TGF-β synthesis or activation. Next, we treated AG490, which is the well-known inhibitor of Janus kinase (JAK), with hydrogen peroxide. AG490 abrogated the CTGF induction by ROS in a dose-dependent manner. The results suggest that JAK-2/-3 seems to be involved in the enhanced CTGF mRNA expression by hydrogen peroxide. In this report, we present that hydrogen peroxide is a novel inducer of CTGF gene expression and that JAK-2/-3 activation seems to play a role in CTGF induction.