Mast cells (MCs) are sentinels located in tissues proximal to the outside environment. They alert the immune system to invasion of various pathogens and create an inflammatory milieu. Upon activation via the family of Toll-IL-1-receptors (TIRs), MCs produce pro-inflammatory cytokines. In order to provide a response, which is appropriate to the type of pathogen and the local tissue MCs need to modulate their cytokine profile by integrating input from the surrounding milieu. We have previously shown that activation of the PI3K pathway augments the secretion of TNF-α and IL-6 but attenuates the synthesis of IL-1β in TIR-ligand-stimulated MCs [1]. Thus, the PI3K pathway represents a basic mechanism to differentially modulate NF-κB-driven, pro-inflammatory cytokines. We are particularly interested in the molecular mechanism that negatively regulates IL-1β downstream of the PI3K. To study this we employ genetic and pharmacological approaches as well as co-stimulation experiments with stimuli that elicit a robust PI3K activation e.g. antigen, steel factor (SF), or IGF-1.

Our results indicate that PI3K-dependent regulation of IL-1β expression is mainly facilitated via Akt-dependent inactivation of the transcription factor FoxO1. Inhibition of Akt augments the TIR-ligand-induced IL-1β synthesis and mimics inhibition of PI3K. In line with this finding, IL-1β production is attenuated when FoxO1 is inhibited. Furthermore, we are interested in the exact PI3K isoforms that are engaged by the TIR receptors themselves or by the co-stimulatory receptors and whether these depend on the Akt-FoxO1 axis to modulate the TIR-induced cytokines in MCs. 

These results may reveal a basic PI3K-dependent mechanism that allows MCs to bias their cytokine profile according to the (patho-)physiological milieu. This will be of relevance for inflammatory responses in the context of cancer and allergic diseases, amongst others.