Btk is a positive regulator in the TREM-1/DAP12 signaling pathway.
In: Blood, Jg. 118 (2011-07-28), Heft 4, S. 936
academicJournal
Zugriff:
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 knockdown, phosphorylation of Erk1/2 and PLCγ1 and Ca²⁺ mobilization were reduced after TREM-1 stimulation. Importantly, TREM-1-induced production of the pro-inflammatory cytokines, TNF-α 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-α 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.
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Btk is a positive regulator in the TREM-1/DAP12 signaling pathway.
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Autor/in / Beteiligte Person: | Ormsby, T ; Schlecker, E ; Ferdin, J ; Tessarz, AS ; Angelisová, P ; Köprülü, AD ; Borte, M ; Warnatz, K ; Schulze, I ; Ellmeier, W ; Horejsí, V ; Cerwenka, A |
Zeitschrift: | Blood, Jg. 118 (2011-07-28), Heft 4, S. 936 |
Veröffentlichung: | 2021- : [New York] : Elsevier ; <i>Original Publication</i>: New York, Grune & Stratton [etc.], 2011 |
Medientyp: | academicJournal |
ISSN: | 1528-0020 (electronic) |
DOI: | 10.1182/blood-2010-11-317016 |
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