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TLR8 triggered gene expression

signalling dataset, transcriptomic dataset

During 2008, we extended all the data regarding TLR3 signaling to TLR8 signaling. Cytokines assays and immunoblotting studies suggest that Src kinases play a crucial role in the control of both MyD88- and TRIF-dependent pathways. We also extended microarray analysis on human MoDC stimulated with R848 (TLR8 agonist), pretreated or not with PP2. In summary, the new generated data on TLR8 triggered gene expression are similar to previous data obtained with TLR3 stimulation, and confirmed that src kinases inhibition is associated to inhibition of key genes in the inflammatory cytokine response. Interestingly, however, the expression of IL-23 p19 was not decreased by PP2. Cytokine assays, indeed, showed that inhibition of Src kinases in human DC stimulated with TLR agonists alone or simultaneously resulted in a dramatic unbalance in the production of IL-12 and IL-23 :since IL-12 impairment was associated to a normal production of IL-23. Moreover the finding that IL-23 is not affected by PP2 treatment was also confirmed in a murine system of Bone Marrow derived Dendritic Cells stimulated with TLR agonists. Real-time qPCR in human MoDC showed that mRNA levels for IL-23A subunit exactly correlated with IL-23 cytokine levels suggesting that the IL-23A chain is the limiting component for the production of a complete IL-23 complex. Moreover, transcriptional analysis showed that the role of Src kinases on specific transcription factors accounts for unbalanced IL-12/IL-23 production.

We will investigate if normal IL-23 production associated to inhibition of IL-12 observed upon stimulation of PP2-treated MoDC would result in a milieu able to induce a Th17 response. Eventually we will evaluate if src kinase inhibitors are able to modulate in-vivo the type of DC driven immune response.

created over 7 years ago (7 December 2009)    last modified over 4 years ago (15 October 2012)   [ RDF Rdf ]   [ RelFinder Relfinder ]