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

• Published in: Blood Vol. 111; no. 4; p. 1781
• Main Authors: Palmer, Christine D, Mutch, Brenda E, Workman, Sarita, McDaid, John P, Horwood, Nicole J, Foxwell, Brian M J
• Format: Journal Article
• Language: English
• Published: United States 15.02.2008
• Subjects: Cell Culture Techniques; Colony-Stimulating Factors - pharmacology; Enzyme-Linked Immunosorbent Assay; Genes, Reporter; Humans; Interleukin-6 - biosynthesis; Interleukin-6 - genetics; Macrophages - cytology; Macrophages - drug effects; Macrophages - enzymology; Macrophages - physiology; Monocytes - physiology; NF-kappa B - metabolism; p38 Mitogen-Activated Protein Kinases - metabolism; Polymerase Chain Reaction; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - physiology; RNA Interference; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - physiology; Transfection; Tumor Necrosis Factor-alpha - genetics
• ISSN: 0006-4971
• DOI: 10.1182/blood-2007-07-102343

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.