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J. Biol. Chem., Vol. 283, Issue 17, 11189-11198, April 25, 2008

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Bruton's Tyrosine Kinase Separately Regulates NFB p65RelA Activation and Cytokine Interleukin (IL)-10/IL-12 Production in TLR9-stimulated B Cells^*

Koon-Guan Lee¹, Shengli Xu¹, Ee-Tsin Wong, Vinay Tergaonkar, and Kong-Peng Lam²

From the Laboratory of Immunology, Bioprocessing Technology Institute and the Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A*STAR), Singapore 138648, Singapore

B lymphocytes express both B cell receptor and Toll-like receptors (TLR). We show here that Bruton's tyrosine kinase (Btk), a critical component in B cell receptor signaling, is also involved in TLR9 signaling in B cells. Stimulation of B cells with TLR9 ligand CpG oligodeoxynucleotide (ODN) leads to transient phosphorylation of Btk, and in the absence of Btk, TLR9-induced proliferation of B cells is impaired. Interestingly, Btk^–/– B cells secrete significantly more interleukin (IL)-12 but much less IL-10 compared with wild type B cells upon TLR9 stimulation. Immunization of Btk^–/– mice with CpG ODN also leads to elevated levels of IL-12 in vivo and consequently, a greater -fold increment in the production of Th1 type IgG2b and IgG3 antibodies in these mice compared with wild type controls. The addition of exogenous recombinant IL-10 could suppress IL-12 production by TLR9-activated Btk^–/– B cells, suggesting that in B cells, Btk negatively regulates IL-12 through the induction of autocrine IL-10 production. TLR9 signaling also leads to the activation of NFB, including the p65RelA subunit in wild type B cells. The lack of Btk signaling affects the activation of NFB and impairs the translocation of the p65RelA subunit to the nucleus of B cells upon TLR9 stimulation. However, p65RelA^–/– B cells could respond similarly to wild type B cells in terms of IL-10 and IL-12 secretion when stimulated with CpG ODN, suggesting that the defect in NFB p65RelA activation is additional to the impairment in cytokine production in TLR9-activated Btk^–/– B cells. Thus, Btk plays an important role in TLR9 signaling and acts separately to regulate NFB RelA activation as well as IL-10 and IL-12 production in B cells.

Received for publication, October 15, 2007 , and in revised form, February 5, 2008.

^* This work was funded by the Biomedical Research Council of A*STAR. We declare no competing financial interests. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to the work.

² To whom correspondence should be addressed. Fax: 65-64642056; E-mail: lam_kong_peng{at}immunol.a-star.edu.sg.

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