IL-6-STAT3 Controls Intracellular MHC Class II αβ Dimer Level through Cathepsin S Activity in Dendritic Cells

• Published in: Immunity (Cambridge, Mass.) Vol. 23; no. 5; pp. 491 - 502
• Main Authors: Kitamura, Hidemitsu, Kamon, Hokuto, Sawa, Shin-ichiro, Park, Sung-Joo, Katunuma, Nobuhiko, Ishihara, Katsuhiko, Murakami, Masaaki, Hirano, Toshio
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.11.2005
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2005.09.010

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.