A role for glycogen synthase kinase-3 in antagonizing mycobacterial immune evasion by negatively regulating IL-10 induction.
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.
Chan
Mabel M P
MM
Department of Pediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
Cheung
Benny K W
BK
Li
James C B
JC
Chan
Lally L Y
LL
Lau
Allan S Y
AS
D000906:Antibodies / Q000494:pharmacology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000276:immunology; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007113:Immunity, Innate / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009000:Monocytes / Q000276:immunology / Q000382:microbiology; D009161:Mycobacterium / Q000276:immunology*; D009164:Mycobacterium Infections / Q000276:immunology* / Q000503:physiopathology; D009163:Mycobacterium bovis / Q000276:immunology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation
D000906:Antibodies; D004791:Enzyme Inhibitors; D006684:HLA-DR Antigens; D016753:Interleukin-10; D007371:Interferon-gamma; D051058:Oncogene Protein v-akt; D038362:Glycogen Synthase Kinase 3