Activation of the PI3K pathway increases TLR-induced @entity637 and @entity777 but reduces XXXX production in mast cells.

@entity10898 @entity26051 @entity558 @entity20216 @entity20721 @entity19 @entity635 @entity2307 @entity777 @entity8932 @entity7424 @entity1990 @entity637
Recognition of bacterial constituents by mast cells (MCs) is dependent on the presence of pattern recognition receptors, such as Toll-like receptors (TLRs). The final cellular response, however, depends on the influence of multiple environmental factors. In the current study we tested the hypothesis that the PI3K-activating ligands insulin-like growth factor-1 ( @entity7424 ), insulin, antigen, and @entity10898 (SF) are able to modulate the @entity1990 -mediated production of proinflammatory cytokines in @entity19 MCs. Costimulation with any of these ligands caused increased @entity558 -triggered secretion of @entity777 and @entity637 , but attenuated the production of @entity635 , though all three cytokines were produced in an NFkB-dependent manner. The pan-specific PI3K-inhibitor @entity2307 reverted the altered production of these cytokines. In agreement, MCs deficient for @entity20216 , a negative regulator of the PI3K pathway, showed augmented secretion of @entity777 / @entity637 and reduced production of @entity635 in response to @entity558 alone. The differential effects of @entity7424 on @entity1990 -mediated cytokine production were also observed in the context of @entity8932 and @entity26051 receptor-mediated MC activation. Importantly, these effects were seen in both bone marrow-derived and peritoneal MCs, suggesting general relevance for MCs. Using pharmacological and genetic tools, we could show that the @entity20721   isoform of PI3K is strongly implicated in SF-triggered suppression of @entity558 -induced @entity635 production. Costimulation with antigen was affected to a lesser extent. In conclusion, NFkB-dependent production of proinflammatory cytokines in MCs is differentially controlled by PI3K-activating ligand/receptor systems.
