Bruton's Tyrosine Kinase Is Required For Lipopolysaccharide-induced Tumor Necrosis Factor {alpha} Production

doi:10.1084/jem.20021845

Published 16 June 2003. doi:10.1084/jem.20021845

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© Rockefeller University Press, 0022-1007/2003/6/1603 $5.00
The Journal of Experimental Medicine, Volume 197, Number 12, 1603-1611

Bruton's Tyrosine Kinase Is Required For Lipopolysaccharide-induced Tumor Necrosis Factor ${alpha}$ Production

Nicole J. Horwood¹, Tara Mahon¹, John P. McDaid¹, Jamie Campbell¹, Hiroyuki Mano², Fionula M. Brennan¹, David Webster³ and Brian M.J. Foxwell¹

¹ Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology and Medicine, London W6 8LH, United Kingdom
² Jichi Medical School, Division of Functional Genomics, Tochigi 329-0498, Japan
³ Royal Free Medical School, Department of Immunology, University College London, London NW3 2QG, United Kingdom

Address correspondence to Brian M.J. Foxwell, Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Charing Cross Campus, ARC Building, 1 Aspenlea Road, London W6 8LH, United Kingdom. Phone: 44-208-383-4444; Fax: 44-208-383-4499; E-mail: b.foxwell{at}ic.ac.uk

Lipopolysaccharide (LPS), a product of Gram-negative bacteria,is potent mediator of tumor necrosis factor (TNF) ${alpha}$ productionby myeloid/macrophage cells. Inhibitors capable of blockingthe signaling events that result in TNF ${alpha}$ production could provideuseful therapeutics for treating septic shock and other inflammatorydiseases. Broad spectrum tyrosine inhibitors are known to inhibitTNF ${alpha}$ production, however, no particular family of tyrosine kinaseshas been shown to be essential for this process. Here we showthat the Bruton's tyrosine kinase (Btk)-deficient mononuclearcells from X-linked agammaglobulinemia patients have impairedLPS-induced TNF ${alpha}$ production and that LPS rapidly induces Btkkinase activity in normal monocytes. In addition, adenoviraloverexpression of Btk in normal human monocytes enhanced TNF ${alpha}$ production. We examined the role of Btk in TNF ${alpha}$ production usingluciferase reporter adenoviral constructs and have establishedthat overexpression of Btk results in the stabilization of TNF ${alpha}$ mRNA via the 3' untranslated region. Stimulation with LPS alsoinduced the activation of related tyrosine kinase, Tec, suggestingthat the Tec family kinases are important components for LPS-inducedTNF ${alpha}$ production. This study provides the first clear evidencethat tyrosine kinases of the Tec family, in particular Btk,are key elements of LPS-induced TNF ${alpha}$ production and consequentlymay provide valuable therapeutic targets for intervention ininflammatory conditions.

Key Words: tyrosine kinase • adenovirus • TNF ${alpha}$ • macrophage • X-linked agammaglobulinemia

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