Role of glycogen synthase kinase 3 (GSK-3) in innate immune response of human immature dendritic cells to Aspergillus fumigatus

Med Mycol. 2010 Jun;48(4):589-97. doi: 10.3109/13693780903420625.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminophenols / pharmacology
  • Aspergillosis / immunology
  • Aspergillus fumigatus / immunology*
  • Dendritic Cells / enzymology
  • Dendritic Cells / immunology*
  • Dendritic Cells / microbiology
  • Enzyme-Linked Immunosorbent Assay
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 / genetics
  • Glycogen Synthase Kinase 3 / physiology*
  • Humans
  • Immunity, Innate / immunology
  • Interleukin-10 / biosynthesis
  • Lithium Chloride / pharmacology
  • Maleimides / pharmacology
  • Polymorphism, Single Nucleotide / genetics
  • RNA, Small Interfering / pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Necrosis Factor-alpha / biosynthesis

Substances

  • 3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione
  • Aminophenols
  • Maleimides
  • RNA, Small Interfering
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Glycogen Synthase Kinase 3
  • Lithium Chloride