Role of glycogen synthase kinase 3 (GSK-3) in innate immune response of human immature dendritic cells to Aspergillus fumigatus.
Dysregulation of the Th1/Th2 cytokine balance and a switch to a Th2 immune response contribute to the development of and the unfavorable outcome from invasive aspergillosis (IA). We explore in this paper the role of glycogen synthase kinase 3 (GSK-3) in human immature dendritic cells (iDCs) relative to infection caused by A. fumigatus by the use of GSK-3 inhibitors (LiCl, SB415286) and RNA interference technology. In iDCs exposed to A. fumigatus germ tubes, inhibition of GSK-3 with LiCl or SB415286, as well as transfection with small interfering RNA, led to markedly elevated expression of the anti-inflammatory cytokine IL-10. In contrast, pro-inflammatory cytokine response was only partially regulated by GSK-3. Screening of patients after allogeneic stem cell transplantation (with or without IA) for the presence of genetic markers (rs334558, rs6438552) in the GSK-3 gene revealed no significant association with an increased risk for IA. In conclusion, GSK-3 might be involved in the regulation of the anti-inflammatory response of iDCs in the context of infections due to A. fumigatus, albeit the exact mechanisms have to be clarified in future experiments.
Spinnler
Katrin
K
Universität Würzburg, Medizinische Klinik & Poliklinik II, Germany.
Mezger
Markus
M
Steffens
Michael
M
Sennefelder
Helga
H
Kurzai
Oliver
O
Einsele
Hermann
H
Loeffler
Juergen
J
D000627:Aminophenols / Q000494:pharmacology; D001228:Aspergillosis / Q000276:immunology; D001232:Aspergillus fumigatus / Q000276:immunology*; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology* / Q000382:microbiology; D004797:Enzyme-Linked Immunosorbent Assay; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis; D018021:Lithium Chloride / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
C417520:3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione; D000627:Aminophenols; D008301:Maleimides; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride