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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.

Type

Journal article

Journal

Blood

Publication Date

02/2008

Volume

111

Pages

1781 - 1788

Addresses

Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College London, London, UK.

Keywords

Monocytes, Macrophages, Humans, p38 Mitogen-Activated Protein Kinases, Tumor Necrosis Factor-alpha, NF-kappa B, Colony-Stimulating Factors, Interleukin-6, Enzyme-Linked Immunosorbent Assay, Cell Culture Techniques, Transfection, Polymerase Chain Reaction, RNA Interference, Genes, Reporter, Toll-Like Receptor 4, Protein-Tyrosine Kinases