Abstracts (complete list) - Wissenschaft Online

Tereza Havlova, Anja Tessarz, Vaclav Horejsi, Adelheid Cerwenka
Identification of Key-Players in TREM1/DAP12 Signaling
Pathway
Triggering Receptor Expressed on Myeloid cells (TREM-1) is a recently described
receptor expressed by monocytes and neutrophils, which plays an important role during
immune responses to microbial infection. The engagement of TREM-1 leads to the
production of pro-inflammatory cytokines such as TNF-α and IL-8 and thereby
contributes to inflammatory conditions. TREM-1 associates with the ITAM-containing
adapter DNAX Activation Protein of 12 kDa (DAP12). In general, ITAM-mediated signals
lead to cell activation, although DAP12 was recently implicated in inhibitory signaling in
mouse macrophages and dendritic cells.
So far, the downstream signaling pathways following receptor triggering have not been
well characterized. Recently, we identified NTAL/LAB/LAT2 as an important gate-keeper
of TREM-1/DAP12-induced signaling in myeloid cells. This transmembrane adaptor
protein is phosphorylated upon TREM-1 ligation in a myelo-monocytic cell line and
primary human granulocytes. Using siRNA mediated knock-down to decrease NTAL
expression levels, we observed enhancement of ERK 1/2 phosphorylation, delay in Ca 2+
mobilization and a substantial decrease in TNF-α and IL-8 production after TREM-1
stimulation.
We are currently focusing on the identification of proteins associated with NTAL in
context of the TREM-1/DAP12 signaling pathway. In addition, we are analyzing proteins,
which become phosphorylated upon TREM-1 triggering, via mass spectrometry to obtain
new insights about the known and yet unknown key-players in this signaling pathway.
The knowledge gained by this study could help to define novel therapeutic targets for
the treatment of inflammatory diseases and sepsis.