Src kinases are required for a balanced production of IL-12/IL-23 in human dendritic cells activated by Toll-like receptor agonists.
BACKGROUND
Pathogen recognition by dendritic cells (DC) is crucial for the initiation of both innate and adaptive immune responses. Activation of Toll-like Receptors (TLRs) by microbial molecular patterns leads to the maturation of DC, which present the antigen and activate T cells in secondary lymphoid tissues. Cytokine production by DC is critical for shaping the adaptive immune response by regulating T helper cell differentiation. It was previously shown by our group that Src kinases play a key role in cytokines production during TLR4 activation in human DC.


RESULTS
In this work we investigated the role of Src kinases during different TLRs triggering in human monocyte-derived DC (MoDC). We found that Src family kinases are important for a balanced production of inflammatory cytokines by human MoDC upon stimulation of TLR3 and 8 with their respective agonists. Disruption of this equilibrium through pharmacological inhibition of Src kinases alters the DC maturation pattern. In particular, while expression of IL-12 and other inflammatory cytokines depend on Src kinases, the induction of IL-23 and co-stimulatory molecules do not. Accordingly, DC treated with Src inhibitors are not compromised in their ability to induce CD4 T cell proliferation and to promote the Th17 subset survival but are less efficient in inducing Th1 differentiation.


CONCLUSIONS
We suggest that the pharmacological modulation of DC maturation has the potential to shape the quality of the adaptive immune response and could be exploited for the treatment of inflammation-related diseases.
Kuka
Mirela
M
Novartis Vaccines, Siena, Italy.
Baronio
Roberta
R
Valentini
Sara
S
Monaci
Elisabetta
E
Muzzi
Alessandro
A
Aprea
Susanna
S
De Gregorio
Ennio
E
D'Oro
Ugo
U
D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D018664:Interleukin-12 / Q000096:biosynthesis*; D053759:Interleukin-23 / Q000096:biosynthesis*; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D011743:Pyrimidines / Q000494:pharmacology; D051196:Toll-Like Receptor 3 / Q000819:agonists / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000378:metabolism; D051200:Toll-Like Receptor 8 / Q000819:agonists / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists* / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
C412373:AG 1879; D007093:Imidazoles; D053759:Interleukin-23; D011743:Pyrimidines; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051200:Toll-Like Receptor 8; D051193:Toll-Like Receptors; D018664:Interleukin-12; D019061:src-Family Kinases; C402365:resiquimod