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Published 27 March 2006. doi:10.1083/jcb.200508058
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 172, Number 7, 1057-1068
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Article

 CpG-induced tyrosine phosphorylation occurs via a TLR9-independent mechanism and is required for cytokine secretion

Miguel A. Sanjuan1, Navin Rao1, Kuei-Tai A. Lai1, Yin Gu1, Siquan Sun1, Anja Fuchs2, Wai-Ping Fung-Leung1, Marco Colonna2, and Lars Karlsson1

1 Johnson & Johnson Pharmaceutical Research and Development, L.L.C., San Diego, CA 92121
2 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110

Correspondence to Lars Karlsson: lkarlsso{at}prdus.jnj.com

Toll-like receptors (TLRs) recognize molecular patterns preferentially expressed by pathogens. In endosomes, TLR9 is activated by unmethylated bacterial DNA, resulting in proinflammatory cytokine secretion via the adaptor protein MyD88. We demonstrate that CpG oligonucleotides activate a TLR9-independent pathway initiated by two Src family kinases, Hck and Lyn, which trigger a tyrosine phosphorylation–mediated signaling cascade. This cascade induces actin cytoskeleton reorganization, resulting in cell spreading, adhesion, and motility. CpG-induced actin polymerization originates at the plasma membrane, rather than in endosomes. Chloroquine, an inhibitor of CpG-triggered cytokine secretion, blocked TLR9/MyD88-dependent cytokine secretion as expected but failed to inhibit CpG-induced Src family kinase activation and its dependent cellular responses. Knock down of Src family kinase expression or the use of specific kinase inhibitors blocked MyD88-dependent signaling and cytokine secretion, providing evidence that tyrosine phosphorylation is both CpG induced and an upstream requirement for the engagement of TLR9. The Src family pathway intersects the TLR9–MyD88 pathway by promoting the tyrosine phosphorylation of TLR9 and the recruitment of Syk to this receptor.

M.A. Sanjuan's present address is Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105.

Abbreviations used in this paper: CpG, deoxycytidyl-deoxyguanosine; DC, dendritic cell; GpC, deoxyguanosine-deoxycytidyl; IL, interleukin; IRAK, IL-1 receptor–associated kinase; ITAM, immunoreceptor tyrosine-based activation motif; NF, nuclear factor; ODN, oligodeoxynucleotide; PBMC, peripheral blood mononuclear cell; pDC, plasmacytoid DC; pTyr, phosphotyrosine; SFK, Src family kinase; siRNA, small interfering RNA; TLR, Toll-like receptor.


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