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

Christine D Palmer, Brenda E Mutch, Sarita Workman, John P McDaid, Nicole J Horwood, Brian M J Foxwell

Research output: Contribution to journalArticlepeer-review

54 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1781-1788
Number of pages8
JournalBlood
Volume111
Issue number4
Early online date8 Feb 2008
DOIs
Publication statusPublished - 15 Feb 2008

Keywords

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

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