Thioredoxin superfamily and thioredoxin-inducing agents

Mammalian thioredoxin (TRX) with redox-active dithiol in the active site plays multiple roles in intracellular signaling and resistance against oxidative stress. TRX is induced by a variety of stresses including infectious agents as well as hormones and chemicals. TRX is secreted from activated cells such as HTLV-I-transformed T-cells as a redox-sensitive molecule with cytokine-like and chemokine-like activities. The promoter of the TRX gene contains a series of stress-responsive elements. In turn, TRX promotes activation of transcription factors such as NF-kappa B, AP-1, and p53. We have reported that natural substances including estrogen, prostaglandins, and cAMP induce mRNA, protein, and secretion of TRX. These agents seemed to exert their physiological functions including cytoprotective actions partly through the induction of TRX without massive oxidative stress, which induces TRX strongly as well as other stress proteins. We report here a new TRX inducer substance, geranylgeranylacetone (GGA), which is originally derived from a natural plant constituent and has been used in the clinical field as an anti-ulcer drug. We have demonstrated that GGA induces the messenger RNA and protein of TRX and affects the activation of transcription factors, AP-1 and NF-kappa B, and that GGA blunted ethanol-induced cytotoxicity of cultured hepatocytes and gastrointestine mucosal cells. We will discuss a possible novel molecular mechanism of GGA, which is to protect cells via the induction of TRX and activation of transcription factors such as NF-kappa B and AP-1. Identification of the particular TRX-inducing components may contribute to the elucidation of the molecular basis of the "French Paradox," in which good red wines are beneficial for the cardiovascular system.