Fiebiger Edda, Maehr René, Villadangos José, Weber Ekkehard, Erickson Ann, Bikoff Elizabeth, Ploegh Hidde L, Lennon-Duménil Ana-Maria
Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
J Exp Med. 2002 Nov 4;196(9):1263-9. doi: 10.1084/jem.20020762.
Secretion of proteases is critical for degradation of the extracellular matrix during an inflammatory response. Cathepsin (Cat) S and L are the major elastinolytic cysteine proteases in mouse macrophages. A 65 amino acid segment of the p41 splice variant (p41(65aa)) of major histocompatibility complex class II-associated invariant chain (Ii) binds to the active site of CatL and permits the maintenance of a pool of mature enzyme in endosomal compartments of macro-phages and dendritic cells (DCs). Here we show that interaction of p41(65aa) with mature CatL allows extracellular accumulation of the active enzyme. We detected mature CatL as a complex with p41(65aa) in culture supernatants from antigen-presenting cells (APCs). Extracellular accumulation of mature CatL is up-regulated by inflammatory stimuli as observed in interferon (IFN)-gamma-treated macrophages and lipopolysaccharide (LPS)-activated DCs. Despite the neutral pH of the extracellular milieu, released CatL associated with p41(65aa) is catalytically active as demonstrated by active site labeling and elastin degradation assays. We propose that p41(65aa) stabilizes CatL in the extracellular environment and induces a local increase in the concentration of matrix-degrading enzymes during inflammation. Through its interaction with CatL, Ii may therefore control the migratory response of APCs and/or the recruitment of effectors of the inflammatory response.
蛋白酶的分泌对于炎症反应期间细胞外基质的降解至关重要。组织蛋白酶（Cat）S和L是小鼠巨噬细胞中主要的弹性蛋白酶解半胱氨酸蛋白酶。主要组织相容性复合体II类相关恒定链（Ii）的p41剪接变体（p41(65aa)）的一个65个氨基酸的片段与CatL的活性位点结合，并允许在巨噬细胞和树突状细胞（DCs）的内体区室中维持成熟酶库。在此我们表明，p41(65aa)与成熟CatL的相互作用允许活性酶在细胞外积累。我们在抗原呈递细胞（APC）的培养上清液中检测到成熟的CatL与p41(65aa)形成复合物。如在干扰素（IFN）-γ处理的巨噬细胞和脂多糖（LPS）激活的DCs中所观察到的，炎症刺激上调了成熟CatL的细胞外积累。尽管细胞外环境的pH呈中性，但通过活性位点标记和弹性蛋白降解试验证明，与p41(65aa)相关的释放的CatL具有催化活性。我们提出，p41(65aa)在细胞外环境中稳定CatL，并在炎症期间诱导基质降解酶浓度的局部增加。因此，通过其与CatL的相互作用，Ii可能控制APC的迁移反应和/或炎症反应效应器的募集。
