A role for STAT3 and cathepsin S in IL-10 down-regulation of IFN-gamma-induced MHC class II molecule on primary human blood macrophages.
IL-10, a potent anti-inflammatory cytokine, activates its primary mediator STAT3 to exert inhibitory effects on activated immune response. It has been reported that IFN-gamma signaling can be suppressed by IL-10, which deactivates macrophages and suppresses cell-mediated antigen presentation. Cathepsin S, a cysteine protease, plays a significant role in the antigen processing. We hypothesize that the IL-10-induced and STAT3-mediated signaling pathway interferes with IFN-gamma-induced immune responses in primary human blood macrophages. Here, we investigated whether IL-10 perturbs MHC-II levels via its effect on cathepsin S expression in antigen processing. We showed that the expression of cathepsin S and MHC-II, inducible by IFN-gamma, was down-regulated in the presence of IL-10. Additionally, we revealed that the inhibitory effect of IL-10 was demonstrated to be independent of the classical IFN-gamma-induced JAK2/STAT1 signaling cascade or the NF-kappaB pathway. Following STAT3 suppression with specific siRNA, the expression of IFN-gamma-induced surface MHC-II antigens and cathepsin S levels was restored, even in the presence of IL-10. Taken together, our results demonstrated that the immunosuppressive effects of IL-10-STAT3 on MHC-II antigen presentation may occur via the inhibition of cathepsin S expression.
Chan
Lally L Y
LL
Cytokine Biology Group, Department of Pediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Queen Mary Hospital, 102 Pokfulam Rd., Hong Kong SAR, China.
Cheung
Benny K W
BK
Li
James C B
JC
Lau
Allan S Y
AS
D001773:Blood Cells; D002403:Cathepsins / Q000235:genetics* / Q000502:physiology; D015536:Down-Regulation / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D006801:Humans; D007109:Immunity; D007371:Interferon-gamma; D016753:Interleukin-10 / Q000494:pharmacology*; D008264:Macrophages / Q000276:immunology*; D050796:STAT3 Transcription Factor / Q000502:physiology*
D000949:Histocompatibility Antigens Class II; D050796:STAT3 Transcription Factor; D016753:Interleukin-10; D007371:Interferon-gamma; D002403:Cathepsins; C028217:cathepsin S