TUMOR-NECROSIS-FACTOR AND INTERLEUKIN-1 LEAD TO PHOSPHORYLATION AND LOSS OF I-KAPPA-B-ALPHA - A MECHANISM FOR NF-KAPPA-B ACTIVATION

Nuclear factor kappaB (NF-kappaB) is a critical regulator of several genes which are involved in immune and inflammation responses. NF-kappaB, consisting of a 50-kDa protein (p50) and a 65-kDa protein (p65), is bound to a cytoplasmic retention protein called IkappaB. 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-kappaB 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-kappaB activation is through the phosphorylation and subsequent loss of its inhibitor, IkappaBalpha We also show that both IkappaBalpha loss and NF-kappaB activation are inhibited in the presence of antioxidants, demonstrating that the loss of IkappaBalpha is a prerequisite for NF-kappaB activation. Finally, we demonstrate that IkappaBalpha is rapidly resynthesized after loss, indicating that an autoregulatory mechanism is involved in the regulation of NF-kappaB function. We propose a mechanism for the activation of NF-kappaB through the modification and loss of IkappaBalpha, thereby establishing its role as a mediator of NF-kappaB activation.