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

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

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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.

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