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    Keywords: EXPRESSION ; GENE ; MICE ; INFECTION ; HUMAN NEUTROPHILS ; KAPPA-B ACTIVATION ; INFLAMMATORY RESPONSES ; myeloid cells ; SEPTIC SHOCK ; BRUTONS TYROSINE KINASE ; FAMILY KINASES ; RECEPTOR-MEDIATED ACTIVATION ; TEC KINASE ; X-LINKED AGAMMAGLOBULINEMIA
    Abstract: The triggering receptor expressed on myeloid cells 1 (TREM-1) has been implicated in the production of proinflammatory cytokines and chemokines during bacterial infection and sepsis. For downstream signal transduction, TREM-1 is coupled to the ITAM-containing adaptor DAP12. Here, we demonstrate that Bruton tyrosine kinase (Btk), a member of the Tec kinases, becomes phosphorylated upon TREM-1 triggering. In U937-derived cell lines, in which expression of Btk was diminished by shRNA-mediated knock-down, phosphorylation of Erk1/2 and PLC gamma 1 and Ca(2+) mobilization were reduced after TREM-1 stimulation. Importantly, TREM-1-induced production of the pro-inflammatory cytokines, TNF-alpha and IL-8, and up-regulation of activation/differentiation cell surface markers were impaired in Btk knockdown cells. Similar results were obtained upon TREM-1 stimulation of BMDCs of Btk(-/-) mice. The analysis of cells containing Btk mutants revealed that intact membrane localization and a functional kinase domain were required for TREM-1-mediated signaling. Finally, after TREM-1 engagement, TNF-alpha production by PBMCs was reduced in the majority of patients suffering from X-linked agammaglobulinemia (XLA), a rare hereditary disease caused by mutations in the BTK gene. In conclusion, our data identify Btk as a positive regulator in the ITAM-mediated TREM-1/DAP12 pathway and suggest its implication in inflammatory processes.
    Type of Publication: Journal article published
    PubMed ID: 21659545
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