Reciprocal regulation of IL-23 and IL-12 following co-activation of Dectin-1 and TLR signaling pathways.
Recognition of microbial products by germ-line-encoded PRR initiates immune responses, but how PRR mediate specific host responses to infectious agents is poorly understood. We and others have proposed that specificity is achieved by collaborative responses mediated between different PRR. One such example comprises the fungal beta-glucan receptor Dectin-1, which collaborates with TLR to induce TNF production. We show here that collaborative responses mediated by Dectin-1 and TLR2 are more extensive than first appreciated, and result in enhanced IL-23, IL-6 and IL-10 production in DC, while down-regulating IL-12 relative to the levels produced by TLR ligation alone. Such down-regulation occurred with multiple MyD88-coupled TLR, was dependent on signaling through Dectin-1 and also occurred in macrophages. These findings explain how fungi can induce IL-23 and IL-6, while suppressing IL-12, a combination which has previously been shown to contribute to the development of Th17 responses found during fungal infections. Furthermore, these data reveal how the collaboration of different PRR can tailor specific responses to infectious agents.
Dennehy
Kevin M
KM
Institute of Infectious Disease and Molecular Medicine, Clinical Laboratory Sciences Division of Immunology, University of Cape Town, Cape Town, South Africa.
Willment
Janet A
JA
Williams
David L
DL
Brown
Gordon D
GD
D000818:Animals; D015536:Down-Regulation; D007113:Immunity, Innate / Q000276:immunology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D053759:Interleukin-23 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology; D037181:Lectins, C-Type; D008565:Membrane Proteins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D009419:Nerve Tissue Proteins / Q000276:immunology* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000276:immunology; D012313:RNA / Q000737:chemistry / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000072377:Syk Kinase; D051195:Toll-Like Receptor 2 / Q000276:immunology* / Q000378:metabolism; D018183:Transplantation Chimera; D047071:beta-Glucans / Q000276:immunology; D000099181:Dectin-1
D018664:Interleukin-12; D053759:Interleukin-23; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D008565:Membrane Proteins; D053594:Myeloid Differentiation Factor 88; D009419:Nerve Tissue Proteins; D011505:Protein-Tyrosine Kinases; D012313:RNA; D000072377:Syk Kinase; D051195:Toll-Like Receptor 2; D047071:beta-Glucans; D000099181:Dectin-1; C507780:Myd88 protein, mouse; C493486:Tlr2 protein, mouse; C000606897:Syk protein, mouse