Bmx tyrosine kinase regulates TLR4-induced IL-6 production in human macrophages independently of p38 MAPK and NFkapp}B activity

Palmer, Christine D, Mutch, Brenda E, Workman, Sarita, McDaid, John P, Horwood, Nicole J ORCID: https://orcid.org/0000-0002-6344-1677 and Foxwell, Brian M J (2008) Bmx tyrosine kinase regulates TLR4-induced IL-6 production in human macrophages independently of p38 MAPK and NFkapp}B activity. Blood, 111 (4). pp. 1781-1788. ISSN 0006-4971

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Abstract

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-alpha 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-alpha, 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-kappaB 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.

Item Type:	Article
Uncontrolled Keywords:	cell culture techniques,pharmacology,enzyme-linked immunosorbent assay,genes, reporter,humans,biosynthesis,cytology,physiology,metabolism,polymerase chain reaction,genetics,rna interference,genetics,transfection,genetics,metabolism
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
Depositing User:	LivePure Connector
Date Deposited:	06 Mar 2019 10:30
Last Modified:	19 Oct 2023 02:23
URI:	https://ueaeprints.uea.ac.uk/id/eprint/70132
DOI:	10.1182/blood-2007-07-102343

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