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Syk kinase is required for collaborative cytokine production induced through Dectin-1 and Toll-like receptors. 2008
Kevin M Dennehy, and
Gerben Ferwerda, and
Inês Faro-Trindade, and
Elwira Pyz, and
Janet A Willment, and
Philip R Taylor, and
Ann Kerrigan, and
S Vicky Tsoni, and
Siamon Gordon, and
Friederike Meyer-Wentrup, and
Gosse J Adema, and
Bart-Jan Kullberg, and
Edina Schweighoffer, and
Victor Tybulewicz, and
Hector M Mora-Montes, and
Neil A R Gow, and
David L Williams, and
Mihai G Netea, and
Gordon D Brown
Institute of Infectious Disease and Molecular Medicine, Clinical Laboratory Sciences Division of Immunology, University of Cape Town, Cape Town, South Africa.
Recognition of microbial components by germ-line encoded pattern recognition receptors (PRR) initiates immune responses to infectious agents. We and others have proposed that pairs or sets of PRR mediate host immunity. One such pair comprises the fungal beta-glucan receptor, Dectin-1, which collaborates through an undefined mechanism with Toll-like receptor 2 (TLR2) to induce optimal cytokine responses in macrophages. We show here that Dectin-1 signaling through the spleen tyrosine kinase (Syk) pathway is required for this collaboration, which can also occur with TLR4, 5, 7 and 9. Deficiency of either Syk or the TLR adaptor MyD88 abolished collaborative responses, which include TNF, MIP-1alpha and MIP-2 production, and which are comparable to the previously described synergy between TLR2 and TLR4. Collaboration of the Syk and TLR/MyD88 pathways results in sustained degradation of the inhibitor of kappaB (IkappaB), enhancing NFkappaB nuclear translocation. These findings establish the first example of Syk- and MyD88-coupled PRR collaboration, further supporting the concept that paired receptors collaborate to control infectious agents.
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