A role for glycogen synthase kinase-3 in antagonizing mycobacterial immune evasion by negatively regulating IL-10 induction

J Leukoc Biol. 2009 Aug;86(2):283-91. doi: 10.1189/jlb.0708442. Epub 2009 Apr 28.


Mtb dysregulates monocyte/macrophage functions to produce a large amount of the immunosuppressive cytokine IL-10. An important function of IL-10 in promoting Mtb survival is the suppression of antigen presentation of monocytes/macrophages to T cells. This dampens the host immune responses and provides an opportunity for immune evasion. GSK3 has been shown to control the balance between pro- and anti-inflammatory cytokine productions. Here, we investigated whether GSK3 regulates IL-10 expression and mediates a protective role upon live mycobacterial challenge using BCG as a model. Our results showed that BCG increased Akt phosphorylation and inhibited GSK3 activity, resulting in increased IL-10 production. We confirmed further that suppression of GSK3 activities by a specific chemical inhibitor strongly enhanced BCG-induced IL-10 production. We also showed that IL-10 secreted by BCG-infected human PBMo was a major suppressor of subsequent IFN-gamma production by PBMC and HLA-DR expression on PBMo in response to BCG. Neutralization of PBMo-secreted IL-10 by anti-IL-10 antibodies restored the IFN-gamma production and HLA-DR surface expression. Taken together, GSK3 negatively regulates mycobacteria-induced IL-10 production in human PBMo. The kinase may play a role in restoring IFN-gamma secretions and subsequent antigen presentation in response to mycobacterial infection. In conclusion, our results suggest a significant role for GSK3 in guarding against mycobacterial evasion of immunity via IL-10 induction in the host.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies / pharmacology
  • Cells, Cultured
  • Down-Regulation / immunology
  • Enzyme Activation / drug effects
  • Enzyme Activation / immunology
  • Enzyme Inhibitors / pharmacology
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 / physiology*
  • HLA-DR Antigens / metabolism
  • Humans
  • Immune Tolerance / immunology*
  • Immunity, Innate / immunology*
  • Interferon-gamma / metabolism
  • Interleukin-10 / antagonists & inhibitors
  • Interleukin-10 / metabolism*
  • Monocytes / immunology
  • Monocytes / microbiology
  • Mycobacterium / immunology*
  • Mycobacterium Infections / immunology*
  • Mycobacterium Infections / physiopathology
  • Mycobacterium bovis / immunology
  • Oncogene Protein v-akt / metabolism
  • Phosphorylation


  • Antibodies
  • Enzyme Inhibitors
  • HLA-DR Antigens
  • Interleukin-10
  • Interferon-gamma
  • Oncogene Protein v-akt
  • Glycogen Synthase Kinase 3