IL-6-STAT3 controls intracellular MHC class II alphabeta dimer level through cathepsin S activity in dendritic cells.
We found IL-6-STAT3 pathway suppresses MHC class II (MHCII) expression on dendritic cells (DCs) and attenuates T cell activation. Here, we showed that IL-6-STAT3 signaling reduced intracellular MHCII alphabeta dimmer, Ii, and H2-DM levels in DCs. IL-6-mediated STAT3 activation decreased cystatin C level, an endogenous inhibitor of cathepsins, and enhanced cathepsin activities. Importantly, cathepsin S inhibitors blocked reduction of MHCII alphabeta dimer, Ii, and H2-DM in the IL-6-treated DCs. Overexpression of cystatin C suppressed IL-6-STAT3-mediated increase of cathepsin S activity and reduction of MHCII alphabeta dimer, Ii, and H2-DM levels in DCs. Cathepsin S overexpression in DCs decreased intracellular MHCII alphabeta dimer, Ii, and H2-DM levels, LPS-mediated surface expression of MHCII and suppressed CD4(+) T cell activation. IL-6-gp130-STAT3 signaling in vivo decreased cystatin C expression and MHCII alphabeta dimer level in DCs. Thus, IL-6-STAT3-mediated increase of cathepsin S activity reduces the MHCII alphabeta dimer, Ii, and H2-DM levels in DCs, and suppresses CD4(+) T cell-mediated immune responses.
Kitamura
Hidemitsu
H
Laboratory for Cytokine Signaling, RIKEN Research Center for Allergy and Immunology, Yokohama 230-0045, Japan.
Kamon
Hokuto
H
Sawa
Shin-Ichiro
S
Park
Sung-Joo
SJ
Katunuma
Nobuhiko
N
Ishihara
Katsuhiko
K
Murakami
Masaaki
M
Hirano
Toshio
T
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002403:Cathepsins / Q000378:metabolism*; D002478:Cells, Cultured; D015891:Cystatins / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism*; D019281:Dimerization; D000949:Histocompatibility Antigens Class II / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*; D015850:Interleukin-6 / Q000494:pharmacology*; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation
D015891:Cystatins; D000949:Histocompatibility Antigens Class II; D015850:Interleukin-6; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D002403:Cathepsins; C028217:cathepsin S