Vanadate induction of NF-κB involves IκB kinase β and SAPK ERK kinase 1 in macrophages

The present studies investigated the signaling pathways of vanadate, a vanadium ion with +5 oxidation state, to activate NF-kappa B transcription factor, a pivotal regulator of inflammatory responses. Treatment of macrophages with vanadate results in the activation of both NF-kappa B and c-Jun N-terminal kinase (JNK), The activity of a recently identified cellular kinase, I kappa B kinase-beta (IKK beta), was significantly elevated concomitant with the increased degradation of I kappa B alpha and enhanced NF-kappa B activity in cells exposed to vanadate, To determine whether the IKK pathway and JNK pathway are interconnected or bifurcate upon vanadate stimulation, cells were transfected with either a kinase inactive form of IKK beta or a kinase inactive form of SAPK/ERK kinase 1 (SEK1), Inactive IKK beta was able to block vanadate-induced degradation of I kappa B alpha, yet it was unable to influence the activation of JNK by vanadate, Conversely, blockage of JNK activation by transfection of a kinase-inactive form of SEK1 resulted in partially inhibition of vanadate-induced I kappa B alpha degradation. Both vanadate-induced degradation of I kappa B alpha and activation of JNK were potently inhibited by pretreatment of cells with N-acetylcysteine or dimercaprol, These results demonstrate that early activation of stress kinases or change of cellular redox states plays a key role in vanadate-induced activation of NF-kappa B and JNK.