title: Dectin-1 interaction with Mycobacterium tuberculosis leads to enhanced IL-12p40 production by splenic dendritic cells.
abstract: Dectin-1 is a fungal pattern recognition receptor that binds to beta-glucans and triggers cytokine production by facilitating interaction with TLR2 or by directly activating spleen tyrosine kinase (Syk). To assess the possible role of Dectin-1 in the innate response to mycobacteria, we used an in vitro system in which IL-12p40 production is measured in splenic dendritic cells (SpDC) following exposure to live Mycobacterium tuberculosis bacilli. Treatment of SpDC with laminarin or glucan phosphate, two molecules known to block Dectin-1-dependent activity, led to a reduction in M. tuberculosis-induced IL-12p40 as well as IL-12p70 production. Moreover, SpDC from Dectin-1-/- chimeric mice displayed reduced IL-12p40 production in response to mycobacteria when compared with Dectin-sufficient DC. Laminarin treatment also inhibited mycobacterial-induced IL-12p40 production in DC from TLR2-/- mice, arguing that Dectin-1 functions independently of TLR2 signaling in this system. Importantly, a Dectin-1 fusion protein was found to directly bind to live mycobacteria in a laminarin-inhibitable manner indicating the presence of ligands for the receptor in the bacterium and laminarin pretreatment resulted in reduced association of mycobacteria to SpDC. In additional experiments, mycobacterial stimulation was shown to be associated with increased phosphorylation of Syk and this response was inhibited by laminarin. Furthermore, pharmacologic inhibition of Syk reduced the M. tuberculosis-induced IL-12p40 response. Together, these findings support a role for Dectin-1 in promoting M. tuberculosis-induced IL-12p40 production by DC in which the receptor augments bacterial-host cell interaction and enhances the subsequent cytokine response through an unknown mechanism involving Syk signaling.
authors.affiliation: Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. rothfuchsa@niaid.nih.gov
authors.forename: Antonio Gigliotti
authors.initials: AG
authors.lastname: Rothfuchs
authors.forename: Andre
authors.initials: A
authors.lastname: Bafica
authors.forename: Carl G
authors.initials: CG
authors.lastname: Feng
authors.forename: Jackson G
authors.initials: JG
authors.lastname: Egen
authors.forename: David L
authors.initials: DL
authors.lastname: Williams
authors.forename: Gordon D
authors.initials: GD
authors.lastname: Brown
authors.forename: Alan
authors.initials: A
authors.lastname: Sher
mesh_terms: D000276:Adjuvants, Immunologic / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D039481:CD11b Antigen / Q000502:physiology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D005936:Glucans; D000960:Hypolipidemic Agents / Q000378:metabolism / Q000494:pharmacology; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D053762:Interleukin-12 Subunit p40 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors; D037181:Lectins, C-Type; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D011134:Polysaccharides / Q000378:metabolism / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000502:physiology; D013154:Spleen / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology; D000072377:Syk Kinase; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics; D000099181:Dectin-1