Keywords:
RECEPTOR
;
CELLS
;
EXPRESSION
;
CELL
;
Germany
;
human
;
TYROSINE KINASE
;
PROTEIN
;
RNA
;
cell line
;
LINES
;
TRANSDUCTION
;
ACTIVATION
;
COMPLEX
;
RESPONSES
;
COMPLEXES
;
CUTTING EDGE
;
DENDRITIC CELLS
;
CELL-LINES
;
PHOSPHORYLATION
;
signal transduction
;
SIGNAL
;
MOUSE
;
PATTERNS
;
SIGNAL-TRANSDUCTION
;
CELL-LINE
;
LINE
;
B-CELLS
;
NATURAL-KILLER-CELLS
;
NK cells
;
cell lines
;
REGULATOR
;
NEUTROPHILS
;
signaling
;
RE
;
PRODUCTS
;
INTERFERENCE
;
RNA INTERFERENCE
;
LEADS
;
CYTOKINE PRODUCTION
;
LEVEL
;
SIGNALS
;
B-CELL
;
immunology
;
DAP12
;
AMPLIFIES INFLAMMATION
;
PHOSPHOLIPASE C-GAMMA-1
Abstract:
The engagement of triggering receptor expressed on myeloid cells 1 (TREM-1) on macrophages and neutrophils leads to TNF-alpha and IL-8 production and enhances inflammatory responses to microbial products. For signal transduction, TREM-1 couples to 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. To date, signals downstream of the TREM-1 and DAP12 complex in myeloid cells are poorly defined. By analyzing receptor-induced tyrosine phosphorylation patterns, we discovered that the ligation of TREM-1 leads to tyrosine phosphorylation of the non-T cell activation linker (NTAL; also called linker of activation in B cells or LAB) in a myelomonocytic cell line and primary human granulocytes. Using RNA interference to decrease the expression levels of NTAL, we demonstrate that in NTAL knockdown cell lines the phosphorylation of ERK1/2 is enhanced. In addition, low levels of NTAL are correlated with decreased and delayed mobilization of Ca2+ after TREM-1 triggering. Most importantly, we demonstrate that NTAL acts as a negative regulator of TNF-alpha and IL-8 production after stimulation via TREM-1. Our results show that activation signals delivered via DAP12 can be counterbalanced by the adaptor NTAL, identifying NTAL as gatekeeper of TREM-1/DAP12-induced signaling in myeloid cells. The Journal of Immunology, 2007, 178: 1991-1999
Type of Publication:
Journal article published
Deep Link:
http://www.dkfz.de/cgi-bin/sel?http://www.dkfz.de/PublicationManager/Show/ShowJournal.aspx%3fpublishedId=5253
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