Abstracts (complete list) - Wissenschaft Online

Martin Schlee, Michael Bscheider, Veit Hornung, Andrea Ablasser, Stefan Endres,
Gunther Hartmann
Contrasting roles of p38 in TLR signaling
Toll-like receptors 7 and 8 are activated by the synthetic compound Resiquimod (R848).
According to previous studies, TLR7/8 stimulation involves NF?B, IRF and MAP kinase
activation, which leads to secretion of proinflammatory cytokines in myeloid cells as well
as type I IFN release in plasmacytoid dendritic cells (PDC).
To further evaluate the role of different MAP kinases, we incubated peripheral blood
mononuclear cells (PBMCs) or murine bone marrow-derived dendritic cells obtained
from a Flt3-ligand (Flt3–L) culture with synthetic inhibitors and monitored cytokine
secretion induced by TLR stimulation.
Here we present data that suggest a negative influence of p38 MAP kinase on IL12
secretion after stimulation with R848 but not LPS. Using the well-characterized selective
chemical p38 inhibitor SB203580 from the family of the pyridinyl imidazoles, we could
dose-dependently increase the amount of IL12 secreted by human monocytes. This
increased cytokine secretion was independent of the Th1-inhibitory cytokine IL10. In
contrast, inhibition of p38 almost completely abolished IFNa production after R848
stimulation of PDCs. Similar results were gained regarding the signaling of murine
myeloid bone marrow-derived dendritic cells (mDC) obtained from a Flt3–L culture. An
increase of IL12 production in the presence of SB203580 after R848 and CpG
stimulation was observed, while IFN alpha secretion by murine Flt3–L PDCs was
strongly inhibited by SB203580. Surprisingly, IL12 secretion by murine Flt3–L PDCs was
not increased but slightly decreased by SB203580, pointing towards a cell type-specific
role of p38 in TLR signaling rather than a target gene-specific signaling.