Distinct role of spleen tyrosine kinase in the early phosphorylation of inhibitor of κBα via activation of the phosphoinositide-3-kinase and Akt pathways

Nuclear factor (NF)-kappa B activation is a critical step in the triggering of inflammatory responses by macrophages. Although numerous investigations have been reported, the precise regulatory mechanisms controlling inflammatory responses mediated by NF-kappa B remain unclear. In this study, we investigated the early signaling events responsible for modulating NF-kappa B activation using various parameters, such as the expression of pro-inflammatory genes and the phosphorylation levels of inhibitor of kappa B alpha (I kappa B alpha) and its upstream kinases. Lipopolysaccharide (LPS) treatment biphasically induced activation of I kappa B alpha phosphorylation at 5 and 30 min, which induced subsequent pro-inflammatory gene expression that was maximized at 45 and 90 min. Of the intracellular signals tested, a series of signaling cascades composed of spleen tyrosine kinase (Syk), phosphoinositide-3-kinase (PI3K), and Akt (protein kinase B) were involved in regulating early phosphorylation of I kappa B alpha, according to biochemical and pharmacological analyses. Therefore, our data suggests that Syk-mediated activation of intracellular signaling in response to LPS may play an important role in LPS-induced inflammatory signaling events. Thus, Syk may be a potential target for the development of potent anti-inflammatory drugs. (C) 2008 Elsevier Ltd. All rights reserved.