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

Abstract

Gene induction by tumor necrosis factor-α (TNFα) or interleukin-1β (IL-1β) is mediated in part by activation of the transcription factor nuclear factor κB (NF-κB), and requires signal adaptor molecules such as TNF receptor-associated factor (TRAFs). The latter interact with the NF-κB-inducing kinase (NIK), which is believed to be part of the IκB kinase complex. Although the precise mechanism is to be elucidated, it is well-known that antioxidant treatments inhibit the inflammatory cytokine-induced NF-κB 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-κB activation. To elucidate the roles of TRX in the signal transduction of the cytokines, we investigated the effects of TRX on NF-κB activation induced by cytokine treatment or by overexpression of the signaling molecules. Our data show that TRX treatment inhibits NF-κB-dependent transcription at the level of downstream of TRAFs and upstream of NIK: TRX inhibited TRAF2-, TRAF5-, and TRAF6-induced NF-κB activation but does not inhibit NIK-, IKKα-, and MEKK-induced activation. In addition, we show that TRX inhibits NF-κB activation in a manner different from that for SAPK (stress activated protein kinase) inhibition.