Convergence of the XXXX target of @entity3446 complex 1- and glycogen synthase kinase 3-b-signaling pathways regulates the innate inflammatory response.

@entity1 @entity32 @entity15080 @entity558 @entity9135 @entity16221 @entity13407 @entity3446 @entity10366 @entity688 @entity9459
The PI3K pathway and its regulation of @entity1 target of @entity3446 complex 1 ( @entity13407 ) and glycogen synthase kinase 3 (GSK3) play pivotal roles in controlling @entity32 . In this article, we show that @entity13407 and @entity9459 converge and that the capacity of @entity13407 to affect the inflammatory response is due to the inactivation of @entity9459 . Inhibition of @entity13407 attenuated GSK3 phosphorylation and increased its kinase activity. Immunoprecipitation and in vitro kinase assays demonstrated that @entity9459 associated with a downstream target of @entity13407 , p85S6K, and phosphorylated @entity9459 . Inhibition of @entity15080 abrogated the phosphorylation of @entity9459 while increasing and decreasing the levels of IL-12 and @entity688 , respectively, in @entity558 -stimulated monocytes. In contrast, the direct inhibition of GSK3 attenuated the capacity of @entity15080 inhibition to influence the levels of @entity688 and IL-12 produced by @entity558 -stimulated cells. At the transcriptional level, @entity13407 inhibition reduced the DNA binding of @entity10366 and this effect was reversed by GSK3 inhibition. As a result, @entity13407 inhibition increased the levels of NF-kB @entity9135 associated with @entity16221 . Inhibition of NF-kB @entity9135 attenuated @entity3446 's ability to influence the levels of pro- or anti-inflammatory cytokine production in monocytes stimulated with @entity558 . These studies identify the molecular mechanism by which @entity13407 affects GSK3 and show that @entity13407 inhibition regulates pro- and anti-inflammatory cytokine production via its capacity to inactivate GSK3.
