title: Syk kinase is required for collaborative cytokine production induced through Dectin-1 and Toll-like receptors.
abstract: 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.
authors.affiliation: Institute of Infectious Disease and Molecular Medicine, Clinical Laboratory Sciences Division of Immunology, University of Cape Town, Cape Town, South Africa.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Dennehy
authors.forename: Gerben
authors.initials: G
authors.lastname: Ferwerda
authors.forename: Inês
authors.initials: I
authors.lastname: Faro-Trindade
authors.forename: Elwira
authors.initials: E
authors.lastname: Pyz
authors.forename: Janet A
authors.initials: JA
authors.lastname: Willment
authors.forename: Philip R
authors.initials: PR
authors.lastname: Taylor
authors.forename: Ann
authors.initials: A
authors.lastname: Kerrigan
authors.forename: S Vicky
authors.initials: SV
authors.lastname: Tsoni
authors.forename: Siamon
authors.initials: S
authors.lastname: Gordon
authors.forename: Friederike
authors.initials: F
authors.lastname: Meyer-Wentrup
authors.forename: Gosse J
authors.initials: GJ
authors.lastname: Adema
authors.forename: Bart-Jan
authors.initials: BJ
authors.lastname: Kullberg
authors.forename: Edina
authors.initials: E
authors.lastname: Schweighoffer
authors.forename: Victor
authors.initials: V
authors.lastname: Tybulewicz
authors.forename: Hector M
authors.initials: HM
authors.lastname: Mora-Montes
authors.forename: Neil A R
authors.initials: NA
authors.lastname: Gow
authors.forename: David L
authors.initials: DL
authors.lastname: Williams
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.forename: Gordon D
authors.initials: GD
authors.lastname: Brown
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D018836:Inflammation Mediators / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D037181:Lectins, C-Type; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D000072377:Syk Kinase; D051195:Toll-Like Receptor 2 / Q000502:physiology*; D000099181:Dectin-1
chemical_list: D016207:Cytokines; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D008024:Ligands; D008565:Membrane Proteins; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; D051195:Toll-Like Receptor 2; D000099181:Dectin-1; C493486:Tlr2 protein, mouse; C000606896:SYK protein, human; C000606897:Syk protein, mouse