However, increased levels of IL-10 could contribute to increased susceptibility towards bacterial infections. see more Furthermore, several studies have demonstrated the influence of the PKB/Akt

signaling cascade on the LPS-driven IL-10 production [35-38]. In analogy to our study (Fig. 5C and Supporting Information Fig. 2D), Schaffer et al. [38] showed that LPS stimulation of human PBMCs after mTOR inhibition resulted in reduced IL-10 secretion, whereas TNF levels were not affected. Furthermore, inhibition of PI3K or mTOR and subsequent LPS-stimulation of human monocytes and dendritic cells and murine macrophages yielded similar results: IL-10 synthesis was abolished and IL-12 production increased [33, 35-37, 39]. The counter-regulation of IL-10 and IL-12 is most likely attributable to IL-10-mediated inhibition of IL-12 production as previously demonstrated in human monocytes [40]. We therefore speculate that IRAK4-silenced selleck inhibitor monocytes resemble rapamycin-treated DCs that display a similar cytokine pattern and defective allogenic T-cell stimulatory capacity [39]. IRAK4-deficiency and mTOR inhibitors

might, thus, counteract the tolerogenic properties of PKB/Akt signaling in innate immune cells resulting inflammation and stomatitis, an important side effect of these drugs [41, 42]. Nevertheless, it remains elusive how TLR signaling is connected to the PI3K/PKB/Akt cascade and how IRAK4 is engaged in this process. In co-immunoprecipitation experiments there was no evidence for a direct

interaction of IRAK4 with PI3K or PKB/Akt (data not shown). However, PI3K is recruited upon TLR activation [43-45]: the cytosolic domain of TLR2 interacted with the regulatory polypeptide p85 of PI3K, resulting in PKB/Akt activation [43] and LPS-induced formation of a TLR4/MyD88/PI3K multiprotein signalosome, which lead to Akt-triggered cytokine secretion in mouse macrophages [44]. Most importantly, a direct interaction of MyD88 with the p85 subunit of PI3K was demonstrated via co-immunoprecipitation, most likely involving an YXXM motif in the TIR domain of MyD88 [44, 45]. Thus, MyD88 could be directly linked to the PI3K/PKB/Akt signaling pathway. We can, however, only speculate that the absence of IRAK4 makes additional MyD88 Avelestat (AZD9668) binding sites available for PI3K and thereby favors PKB/Akt signaling. Binding of IRAK4 could, thus, interfere with MyD88-PI3K interaction by inducing a conformational change in the MyD88 molecule or by competitively blocking MyD88-binding sites for PI3K. Similarly, we cannot exclude that a so far unknown signaling pathway downstream of IRAK4 negatively regulates PKB/Akt signaling. Future work is needed to clarify this matter. By suppressing IL-10 secretion and FoxO3a transcription factor activation, IRAK4 switches the cell from a tolerogenic to a pro-inflammatory phenotype.