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

The NF-kappaB/Rel transcription factors play an important role in the expression of genes involved in B cell development, differentiation and function. Nuclear NF-kappaB is induced in B cells by engagement of either the BCR or CD40 or by stimulation with lipopolysaccharide (LPS). Despite the importance of NF-kappaB to B cell function, little is known about the signaling pathways leading to NF-kappaB activation. In this report we address the role of phosphoinositide 3'-kinase (PI 3-kinase) in BCR- and LPS-induced NF-kappaB 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-kappaB DNA-binding activity. Furthermore, we show that this is achieved via protein kinase C-dependent degradation of IkappaBalpha. Similar analyses reveal that PI 3-kinase is also critical in triggering NF-kappaB DNA-binding activity and IkappaBalpha degradation following LPS stimulation. Interestingly, a PKC inhibitor which blocked the BCR-induced IkappaBalpha degradation had no effect on the degradation of IkappaBalpha 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-kappaB in B cells.