TY - JOUR
T1 - IL-6-STAT3 controls intracellular MHC class II αβ dimer level through cathepsin S activity in Dendritic Cells
AU - Kitamura, Hidemitsu
AU - Kamon, Hokuto
AU - Sawa, Shin Ichiro
AU - Park, Sung Joo
AU - Katunuma, Nobuhiko
AU - Ishihara, Katsuhiko
AU - Murakami, Masaaki
AU - Hirano, Toshio
N1 - Funding Information:
We thank Dr. Takatsu (University of Tokyo) for providing us P25 mice; Dr. Mitchell (University of Kentucky) for pMSCV-IRES-Thy1.1; Dr. Link (Washington University) for pMSCV-DN-STAT3; Dr. Sudo (Torey) for GM-CSF-producing CHO cells; Dr. Kasai (National Institute of Infectious Diseases) for anti-H2-DM, anti-CD74, and anti-MHCII (Y3P) antibodies; and Dr. Saito (RIKEN) for Phoenix cells. We appreciate Ms. Ito, Mr. Yamasaki, Ms. Iketani, and Ms. Hayashi for their excellent technical assistance. We also thank Ms. Masuda, Ms. Kubota, and Ms. Shimura for their excellent secretal assistant. This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology in Japan; the Uehara Foundation; and the Osaka Foundation for the Promotion of Clinical Immunology.
PY - 2005/11
Y1 - 2005/11
N2 - 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 αβ 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 αβ 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 αβ dimer, Ii, and H2-DM levels in DCs. Cathepsin S overexpression in DCs decreased intracellular MHCII αβ 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 αβ dimer level in DCs. Thus, IL-6-STAT3-mediated increase of cathepsin S activity reduces the MHCII αβ dimer, Ii, and H2-DM levels in DCs, and suppresses CD4+ T cell-mediated immune responses.
AB - 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 αβ 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 αβ 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 αβ dimer, Ii, and H2-DM levels in DCs. Cathepsin S overexpression in DCs decreased intracellular MHCII αβ 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 αβ dimer level in DCs. Thus, IL-6-STAT3-mediated increase of cathepsin S activity reduces the MHCII αβ dimer, Ii, and H2-DM levels in DCs, and suppresses CD4+ T cell-mediated immune responses.
UR - http://www.scopus.com/inward/record.url?scp=27744449724&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=27744449724&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2005.09.010
DO - 10.1016/j.immuni.2005.09.010
M3 - Article
C2 - 16286017
AN - SCOPUS:27744449724
SN - 1074-7613
VL - 23
SP - 491
EP - 502
JO - Immunity
JF - Immunity
IS - 5
ER -
