Abstract
Outside of the TLR paradigm, there is little understanding of how pathogen recognition at the cell surface is linked to functional responses in cells of the innate immune system. Recent work in this area demonstrates that the yeast particle zymosan, by binding to the beta-glucan receptor Dectin-1, activates an ITAM-Syk-dependent pathway in dendritic cells, which is required for optimal cytokine production and generation of an oxidative burst. It remains unclear how activation of Syk is coupled to effector mechanisms. In human macrophages, zymosan rapidly activated a calcium-dependent pathway downstream of Dectin-1 and Syk that led to activation of calmodulin-dependent kinase II and Pyk2. Calmodulin-dependent kinase and Pyk2 transduced calcium signals into activation of the ERK-MAPK pathway, CREB, and generation of an oxidative burst, leading to downstream production of IL-10. These observations identify a new calcium-mediated signaling pathway activated by zymosan and link this pathway to both inflammatory and anti-inflammatory responses in macrophages.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Calcium Signaling / drug effects
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Calcium Signaling / immunology*
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Calcium-Calmodulin-Dependent Protein Kinases / physiology
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Calmodulin / antagonists & inhibitors
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Cells, Cultured
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Cyclic AMP Response Element-Binding Protein / blood
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Dimethyl Sulfoxide / pharmacology
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Egtazic Acid / analogs & derivatives
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Egtazic Acid / pharmacology
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Humans
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Interleukin-10 / antagonists & inhibitors
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Interleukin-10 / biosynthesis*
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Interleukin-10 / blood
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / immunology
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Macrophages / immunology*
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Macrophages / metabolism*
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Macrophages / pathology
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Respiratory Burst / drug effects
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Respiratory Burst / immunology*
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Sulfonamides / pharmacology
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ZAP-70 Protein-Tyrosine Kinase / metabolism
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Zymosan / antagonists & inhibitors
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Zymosan / pharmacology*
Substances
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CREB1 protein, human
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Calmodulin
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Cyclic AMP Response Element-Binding Protein
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IL10 protein, human
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Sulfonamides
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Interleukin-10
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Egtazic Acid
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W 7
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Zymosan
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ZAP-70 Protein-Tyrosine Kinase
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ZAP70 protein, human
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Calcium-Calmodulin-Dependent Protein Kinases
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1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid
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Dimethyl Sulfoxide