Kitamura Hidemitsu, Kamon Hokuto, Sawa Shin-Ichiro, Park Sung-Joo, Katunuma Nobuhiko, Ishihara Katsuhiko, Murakami Masaaki, Hirano Toshio
Laboratory for Cytokine Signaling, RIKEN Research Center for Allergy and Immunology, Yokohama 230-0045, Japan.
Immunity. 2005 Nov;23(5):491-502. 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 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.
我们发现白细胞介素-6（IL-6）-信号转导子与转录激活子3（STAT3）信号通路可抑制树突状细胞（DCs）上的主要组织相容性复合体II类分子（MHCII）表达，并减弱T细胞活化。在此，我们表明IL-6-STAT3信号传导降低了DCs细胞内MHCIIαβ二聚体、Ii和H2-DM的水平。IL-6介导的STAT3激活降低了半胱氨酸蛋白酶抑制剂C的水平，半胱氨酸蛋白酶抑制剂C是组织蛋白酶的内源性抑制剂，并增强了组织蛋白酶的活性。重要的是，组织蛋白酶S抑制剂可阻断IL-6处理的DCs中MHCIIαβ二聚体、Ii和H2-DM的减少。半胱氨酸蛋白酶抑制剂C的过表达可抑制IL-6-STAT3介导的组织蛋白酶S活性增加以及DCs中MHCIIαβ二聚体、Ii和H2-DM水平的降低。DCs中组织蛋白酶S的过表达降低了细胞内MHCIIαβ二聚体、Ii和H2-DM的水平、LPS介导的MHCII表面表达，并抑制了CD4(+) T细胞活化。体内IL-6-糖蛋白130-STAT3信号传导降低了DCs中半胱氨酸蛋白酶抑制剂C的表达和MHCIIαβ二聚体水平。因此，IL-6-STAT3介导的组织蛋白酶S活性增加降低了DCs中MHCIIαβ二聚体、Ii和H2-DM的水平，并抑制了CD4(+) T细胞介导的免疫反应。
