Novel stabilin-1 interacting chitinase-like protein (SI-CLP) is up-regulated in alternatively activated macrophages and secreted via lysosomal pathway
Novel stabilin-1 interacting chitinase-like protein (SI-CLP) is up-regulated in alternatively activated macrophages and secreted via lysosomal pathway
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DOI：
10.1182/blood-2005-07-2843
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发表时间：
2006-04-15
期刊：
影响因子：
20.3
通讯作者：
Goerdt, S
中科院分区：
文献类型：
--
作者：
Kzhyshkowska, J;Mamidi, S;Goerdt, S
哺乳动物含糖18结构域蛋白包括催化活性几丁质酶和几丁质酶样蛋白，它们具有参与宿主防御和th2型炎症反应的细胞因子活性。在这里，我们描述了一种新的人类含糖18结构域蛋白，SI-CLP，作为内吞/分选受体稳定蛋白-1的相互作用伙伴。与几丁质酶样细胞因子YKL-39、YKL-40和YM1/2类似，SI-CLP缺乏几丁质结合结构域和催化氨基酸。利用新的单抗1C11，我们证明了SI-CLP在人类选择性活化的巨噬细胞中被分类为晚期内体和分泌溶酶体。SI-CILP与稳定素-1的直接相互作用，它们在反式高尔基网络中的共定位，以及稳定素-1 siRNA处理巨噬细胞中SI-CLP在溶酶体中的分选减少，表明稳定素-1参与了SI-CLP的细胞内分选。巨噬细胞中SI-CLP的表达被Th2细胞因子IL-4和地塞米松强烈上调。这种作用被IFN γ抑制，但不受IL-10的影响。相反，YKL-40的表达受IFN γ诱导，地塞米松抑制。经IL-4处理的巨噬细胞分泌SI-CLP，而与地塞米松共刺激可阻断SI-CLR的分泌并导致细胞内SI-CLR的积累。1C11 mAb在人支气管肺泡灌洗液和外周血白细胞（pbl）中检测到SI-CLP，可用于分析SI-CLP在人类疾病中的作用。
Mammalian Glyco_18-domain-containing proteins include catalytically active chitinases and chitinase-like proteins with cytokine activity involved in host defense and Th2-type inflammatory reactions. Here, we describe a novel human Glyco_18-domain-containing protein, SI-CLP, as an interacting partner of the endocytic/sorting receptor stabilin-1. Similarly to the chitinase-like cytokines YKL-39, YKL-40, and YM1/2, SI-CLP lacks a chitin-binding domain and catalytic amino acids. Using a novel mAb 1C11, we demonstrated that SI-CLP is sorted into late endosomes and secretory lysosomes in human alternatively activated macrophages. The direct interaction of SI-CILP with stabilin-1, their colocalization in the trans-Golgi network, and the reduced sorting of SI-CLP into lysosomes in macrophages treated with stabilin-1 siRNA suggest that stabilin-1 is involved in intracellular sorting of SI-CLP. Expression of SI-CLP in macrophages was strongly up-regulated by the Th2 cytokine IL-4 and by dexamethasone. This effect was suppressed by IFN gamma but not affected by IL-10. In contrast, expression of YKL-40 was induced by IFN gamma and suppressed by dexamethasone. Macrophages treated with IL-4 secreted SI-CLP, while costimulation with dexamethasone blocked secretion and resulted in intracellular accumulation of SI-CLR The 1C11 mAb detected SI-CLP in human bronchoalveolar lavage and peripheral-blood leukocytes (PBLs), and can be used to analyze the role of SI-CLP in human disorders.