Antigen-receptor cross-linking and lipopolysaccharide trigger distinct phosphoinositide 3-kinase-dependent pathways to NF-κB activation in primary B cells.

The NF-κB/Rel transcription factors play an important role in the expression of genes involved in B cell development, differentiation and function. Nuclear NF-κB is induced in B cells by engagement of either the BCR or CD40 or by stimulation with lipopolysaccharide (LPS). Despite the importance of NF-κB to B cell function, little is known about the signaling pathways leading to NF-κB activation. In this report we address the role of phosphoinositide 3′-kinase (PI 3-kinase) in BCR- and LPS-induced NF-κB activation using populations of primary murine resting B cells. Using the specific pharmacological inhibitors of PI 3-kinase, Wortmannin and LY294002, we demonstrate that PI 3-kinase activity is vital for BCR-induced NF-κB DNA-binding activity. Furthermore, we show that this is achieved via protein kinase C-dependent degradation of IκBα. Similar analyses reveal that PI 3-kinase is also critical in triggering NF-κB DNA-binding activity and IκBα degradation following LPS stimulation. Interestingly, a PKC inhibitor which blocked the BCR-induced IκBα degradation had no effect on the degradation of IκBα after LPS stimulation. Taken together, our results indicate the involvement of PI 3-kinase in at least two distinct signaling pathways leading to activation of NF-κB in B cells. [ABSTRACT FROM PUBLISHER]