Human IL4I1 is a secreted L-phenylalanine oxidase expressed by mature dendritic cells that inhibits T-lymphocyte proliferation
Human IL4I1 is a secreted L-phenylalanine oxidase expressed by mature dendritic cells that inhibits T-lymphocyte proliferation
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DOI：
10.1182/blood-2006-07-036210
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发表时间：
2007-07-01
期刊：
影响因子：
20.3
通讯作者：
Castellano, Flavia
中科院分区：
文献类型：
--
作者：
Boulland, Marie-Laure;Marquet, Jeanine;Castellano, Flavia
白细胞介素-4诱导基因1（IL-4 I1）首先被描述为B细胞IL-4诱导基因，并且在原发性纵隔B细胞淋巴瘤中高度表达。我们建立了稳定的HEK 293克隆表达人和小鼠IL 4 I1，以检查其生化特性和功能。这两种蛋白质分泌到培养基中，我们观察到分泌的内源性人IL 4 I1（hIL 4 I1）蛋白在纵隔淋巴瘤B细胞系，MedB-1。我们表明IL 4 I1具有L-氨基酸氧化酶活性，在生理pH下最佳，主要针对苯丙氨酸。免疫组化分析显示次级淋巴器官的生发中心巨噬细胞和炎性髓样细胞染色。在体外，功能酶是最高的成熟树突状细胞（DC），这表明在抗原呈递细胞/T淋巴细胞的串扰的作用。事实上，hIL 4 I1抑制CD 3刺激的T淋巴细胞的增殖，对CD 4（+）和CD 8（+）T细胞具有类似的作用。与此相反，记忆性T细胞更强烈地受到hIL 4 I1及其分解产物H2 O2比幼稚T细胞。hIL 4 I1抑制作用依赖于酶活性和H2 O2产生，并与TCR zeta表达的瞬时下调相关。总之，这些数据表明IL 4 I1作为一种新的免疫调节酶产生的DC。
Interleukin-4-induced gene 1 (IL4I1) was first described as a B-cell IL-4-inducible gene and is highly expressed in primary mediastinal B-cell lymphomas. We established stable HEK293 clones expressing human and mouse IL4I1 to examine their biochemical properties and function. Both proteins were secreted into the culture medium, and we observed the secretion of endogenous human IL4I1 (hIL4I1) protein in a mediastinal lymphoma B-cell line, MedB-1. We showed that IL4I1 has L-amino acid oxidase activity, optimal at physiological pH and primarily directed toward phenylalanine. Immunohistochemical analysis of secondary lymphoid organs showed staining of germinal center macrophages and inflammatory myeloid cells. In vitro, functional enzyme was highest in mature dendritic cells (DCs), suggesting a role in antigen-presenting cell/T-lymphocyte cross-talk. Indeed, hIL4I1 inhibited the proliferation of CD3-stimulated T lymphocytes with a similar effect on CD4(+) and CD8(+) T cells. In contrast, memory T cells were more strongly affected by hIL4I1 and its catabolite H2O2 than naive T cells. hIL4I1 inhibitory effect was dependent on enzymatic activity and H2O2 production and associated with a transient down-regulation of TCR zeta expression. Altogether these data suggest IL4I1 as a new immunomodulatory enzyme produced by DCs.