Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA 23298, USA.
Cell Immunol. 2011;267(1):56-66. doi: 10.1016/j.cellimm.2010.11.004. Epub 2010 Nov 19.
TLR activation is an important component of innate immunity but also contributes to the severity of inflammatory diseases. Cysteine cathepsins (Cat) B, L and S, which are endosomal and lysosomal proteases, participate in numerous physiological systems and are upregulated during various inflammatory disorders and cancers. Macrophages have the highest cathepsin expression and are major contributors to inflammation and tissue damage during chronic inflammatory diseases. We investigated the impact of TLR activation on macrophage Cat B, L and S activities using live-cell enzymatic assays. TLR2, TLR3 and TLR4 ligands increased intracellular activities of these cathepsins in a differential manner. TLR4-induced cytokines increased proteolytic activities without changing mRNA expression of cathepsins or their endogenous inhibitors. Neutralizing antibodies recognizing TNF-α, IL-1β and IFN-β differentially eliminated cathepsin upregulation. These findings indicate cytokines induced by MyD88-dependent and -independent signaling cascades regulate cathepsin activities during macrophage responses to TLR stimulation.
TLR 激活是先天免疫的重要组成部分，但也会导致炎症性疾病的严重程度增加。半胱氨酸组织蛋白酶（Cat）B、L 和 S 是内体和溶酶体蛋白酶，参与许多生理系统，并在各种炎症性疾病和癌症中上调。巨噬细胞具有最高的组织蛋白酶表达水平，是慢性炎症性疾病期间炎症和组织损伤的主要贡献者。我们使用活细胞酶促测定法研究了 TLR 激活对巨噬细胞 Cat B、L 和 S 活性的影响。TLR2、TLR3 和 TLR4 配体以不同的方式增加这些组织蛋白酶的细胞内活性。TLR4 诱导的细胞因子增加了蛋白水解活性，而不改变组织蛋白酶或其内源性抑制剂的 mRNA 表达。识别 TNF-α、IL-1β 和 IFN-β 的中和抗体差异消除了组织蛋白酶的上调。这些发现表明，MyD88 依赖性和非依赖性信号级联诱导的细胞因子在巨噬细胞对 TLR 刺激的反应中调节组织蛋白酶活性。
