Abstracts (complete list) - Wissenschaft Online

Annelies Verbrugge, Adelheid Cerwenka
Dissecting the molecular mechanisms involved in the synergy
of TREM-1 with TLRs
The innate immune system uses a broad spectrum of receptors to detect invading
pathogens. A major class of these receptors are formed by the Toll-Like Receptor (TLR)
s, which directly recognize pathogen-associated molecules and trigger the production of
pro-inflammatory cytokines. In addition, several receptors can act together to enhance
the immune response. One receptor that has been shown to cooperate with TLRs to
induce cytokine production is Triggering Receptor Expressed on Myeloid cells (TREM)-1.
TREM-1 is expressed on neutrophils and monocytes and is upregulated upon stimulation
with LPS. Triggering of TREM-1 results in the production of pro-inflammatory cytokines,
including TNFα. More importantly, TREM-1 synergizes with TLRs in cytokine production.
The goal of our study is to dissect the molecular mechanisms leading to this synergy.
Using quantitative RT-PCR, we found that LPS induced TNFα mRNA in primary human
monocytes. Triggering of TREM-1 did not lead to detectable transcription of TNFα.
However, when TREM-1 was triggered in the presence of LPS a substantial increase in
TNFα mRNA was observed, compared to stimulation with LPS alone. The increase in
TNFα mRNA occurred within the first two hours after stimulation, preceding LPS-induced
upregulation of TREM-1 cell surface expression. Importantly, we found that preengagement
of TREM-1 enhanced TNFα production upon subsequent stimulation with
LPS. In current studies we aim to identify genes involved in the synergy of TREM-1 with
TLRs using microarray-based gene expression profiling. Insight in the molecular
mechanisms leading to synergy will enhance our understanding of the inflammatory
response during sepsis.