Submitted July 23, 2007
Accepted October 21, 2007
Bmx tyrosine kinase regulates TLR4-induced IL-6 production in human macrophages independently of p38 MAPK and NF
B activity
Christine D Palmer, Brenda E Mutch, Sarita Workman, John P McDaid, Nicole J Horwood, and Brian M J Foxwell*
Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College London, London, United Kingdom
Royal Free Medical School, Dept of Immunology, University College London, London, United Kingdom
* Corresponding author; email: b.foxwell{at}imperial.ac.uk.
Chronic inflammation, as seen in conditions such as rheumatoid arthritis (RA) and Crohn's disease, is in part driven by discordant production of inflammatory cytokines such as tumour necrosis factor 
(TNF) and interleukin (IL)-6. Tyrosine kinase activity is essential to LPS-induced cytokine production in monocytes, and previous studies by us and others have implicated a role for the Tec family kinase Bruton's tyrosine kinase (Btk) in inflammatory cytokine production. Here we show that knockdown of Btk using RNAi results in decreased TNF, but not IL-6 production. Further investigations into the signalling mechanisms regulating IL-6 production led to the discovery that the Tec kinase bone marrow tyrosine kinase gene in chromosome X (Bmx) regulates TLR-induced IL-6 production. Our data further showed that Bmx-dependent super-induction of IL-6 does not involve nuclear factor (NF)-
B activity. More detailed investigations of pathways downstream of Bmx signalling revealed that Bmx targets the IL-6 3' untranslated region (UTR) to increase mRNA stabilisation via a novel, thus far undefined p38 mitogen activated protein kinase (MAPK)-independent pathway. These data have important implications for the design of therapeutics targeted against specific cytokines and their regulators in inflammatory disease.
