Thioredoxin Inhibits Tumor Necrosis Factor- or Interleukin-1-Induced NF-κB Activation at a Level Upstream of NF-κB-Inducing Kinase

Gene induction by tumor necrosis factor-alpha (TNF alpha) or interleukin-1 beta (IL-1 beta) is mediated in part the transcription factor nuclear factor kappa B (NF-kappa B), and requires signal adaptor molecules such as TNF receptor-associated factor (TRAFs). The latter interact with the NF-kappa B-inducing kinase (NIK), which is believed to be part of the I kappa B kinase complex. Although the precise mechanism is to be elucidated, it is well-known that antioxidant treatments inhibit the inflammatory cytokine-induced NF-kappa B activation. Thioredoxin (TRX) is a 12-kDa endogenous protein that regulates various cellular functions by modulating the redox state of proteins, overexpression of this molecule inhibits NF-kappa B activation. To elucidate the roles of TRX in the signal transduction of the cytokines, we investigated the effects of TRX on NF-kappa B activation induced by cytokine treatment or by overexpression of the signaling molecules. Our data show that TRX treatment inhibits NF-kappa B-dependent transcription at the level of downstream of TRAFs and upstream of NIK: TRX inhibited TRAF2-, TRAF5-, and TRAF6-induced NF-kappa B activation but does not inhibit NIK-, IKK alpha-, and MEKK-induced activation. In addition, we show that TRX inhibits NF-kappa B activation in a manner different from that for SAPK (stress activated protein kinase) inhibition. Antiox. Redox Signal. 2, 83-92.