In:
Blood, American Society of Hematology, Vol. 111, No. 4 ( 2008-02-15), p. 1781-1788
Kurzfassung:
Chronic inflammation, as seen in conditions such as rheumatoid arthritis and Crohn disease, is in part driven by discordant production of inflammatory cytokines, such as tumor necrosis factor-α and interleukin-6 (IL-6). Tyrosine kinase activity is essential to lipopolysaccharide-induced cytokine production in monocytes, and previous studies by us and others have implicated a role for the Tec kinase Bruton's tyrosine kinase (Btk) in inflammatory cytokine production. Here we show that knockdown of Btk using RNA interference results in decreased tumor necrosis factor-α, but not IL-6 production. Further investigations into the signaling mechanisms regulating IL-6 production led to the discovery that the Tec kinase bone marrow tyrosine kinase gene in chromosome X (Bmx) regulates Toll-like receptor-induced IL-6 production. Our data further showed that Bmx-dependent super-induction of IL-6 does not involve nuclear factor–κB activity. More detailed investigations of pathways downstream of Bmx signaling revealed that Bmx targets the IL-6 3′ untranslated region to increase mRNA stabilization via a novel, thus far undefined, p38 mitogen activated protein kinase-independent pathway. These data have important implications for the design of therapeutics targeted against specific cytokines and their regulators in inflammatory disease.
Materialart:
Online-Ressource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood-2007-07-102343
Sprache:
Englisch
Verlag:
American Society of Hematology
Publikationsdatum:
2008
ZDB Id:
1468538-3
ZDB Id:
80069-7
