Tumor Necrosis Factor and Interleukin-1 Lead to Phosphorylation and Loss of IκBα: a Mechanism for NF-κB Activation

Abstract

Nuclear factor κB (NF-κB) is a critical regulator of several genes which are involved in immune and inflammation responses. NF-κB, consisting of a 50-kDa protein (p50) and a 65-kDa protein (p65), is bound to a cytoplasmic retention protein called IκB. Stimulation of cells with a variety of inducers, including cytokines such as tumor necrosis factor and interleukin-1, leads to the activation and the translocation of p50/65 NF-κB into the nucleus. However, the in vivo mechanism of the activation process remains unknown. Here, we provide the first evidence that the in vivo mechanism of NF-κB activation is through the phosphorylation and subsequent loss of its inhibitor, IκB α. We also show that both IκB α loss and NF-κB activation are inhibited in the presence of antioxidants, demonstrating that the loss of IκB α is a prerequisite for NF-κB activation. Finally, we demonstrate that IκB α is rapidly resynthesized after loss, indicating that an autoregulatory mechanism is involved in the regulation of NF-κB function. We propose a mechanism for the activation of NF-κB through the modification and loss of IκB α, thereby establishing its role as a mediator of NF-κB activation.