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Bruton's Tyrosine Kinase Is Required For Lipopolysaccharide-induced Tumor Necrosis Factor 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) production by myeloid/macrophage cells. Inhibitors capable of blocking the signaling events that result in TNF production could provide useful therapeutics for treating septic shock and other inflammatory diseases. Broad spectrum tyrosine inhibitors are known to inhibit TNF production, however, no particular family of tyrosine kinases has been shown to be essential for this process. Here we show that the Bruton's tyrosine kinase (Btk)-deficient mononuclear cells from X-linked agammaglobulinemia patients have impaired LPS-induced TNF production and that LPS rapidly induces Btk kinase activity in normal monocytes. In addition, adenoviral overexpression of Btk in normal human monocytes enhanced TNF production. We examined the role of Btk in TNF production using luciferase reporter adenoviral constructs and have established that overexpression of Btk results in the stabilization of TNF mRNA via the 3' untranslated region. Stimulation with LPS also induced the activation of related tyrosine kinase, Tec, suggesting that the Tec family kinases are important components for LPS-induced TNF production. This study provides the first clear evidence that tyrosine kinases of the Tec family, in particular Btk, are key elements of LPS-induced TNF production and consequently may provide valuable therapeutic targets for intervention in inflammatory conditions.

Key Words: tyrosine kinase • adenovirus • TNF • macrophage • X-linked agammaglobulinemia

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