Horiuchi Keisuke, Morioka Hideo, Takaishi Hironari, Akiyama Haruhiko, Blobel Carl P, Toyama Yoshiaki
Department of Anti-aging Orthopedic Research, Keio University, School of Medicine, Shinjuku-ku, Tokyo, Japan.
J Immunol. 2009 Jun 15;182(12):7408-14. doi: 10.4049/jimmunol.0801931.
FLT3 ligand (FLT3L) has diverse roles in the hematopoietic system, which include stimulating proliferation of hematopoietic precursors and development of NK cells and dendritic cells. FLT3L is initially synthesized as a membrane-bound protein, which must be cleaved to become a soluble growth factor. However, little is known about the enzyme involved in the proteolytic release of FLT3L. In the current study, we show that shedding of FLT3L is metalloprotease-dependent, and that this proteolytic activity was abolished in fibroblasts lacking TNF-alpha converting enzyme (TACE) and could be rescued by reintroducing wild-type TACE in these cells. Moreover, we found that cells derived from the thymus of conditional TACE-deficient mice produce less FLT3L, and that serum FLT3L levels in these TACE mutant mice are significantly lower, both after LPS treatment and in the absence of such a challenge, further corroborating the relevance of TACE as FLT3L sheddase in vivo. Considering the involvements of FLT3 and FLT3L in hematopoietic malignancies and stem cell mobilization, the identification of the enzyme involved in FLT3L shedding may have important clinical implications.
FLT3配体（FLT3L）在造血系统中具有多种作用，包括刺激造血前体细胞的增殖以及自然杀伤细胞和树突状细胞的发育。FLT3L最初以膜结合蛋白的形式合成，必须经过切割才能成为可溶性生长因子。然而，关于参与FLT3L蛋白水解释放的酶知之甚少。在本研究中，我们表明FLT3L的脱落依赖于金属蛋白酶，并且这种蛋白水解活性在缺乏肿瘤坏死因子-α转换酶（TACE）的成纤维细胞中被消除，而在这些细胞中重新引入野生型TACE可以恢复这种活性。此外，我们发现来自条件性TACE缺陷小鼠胸腺的细胞产生的FLT3L较少，并且在脂多糖处理后以及在没有这种刺激的情况下，这些TACE突变小鼠的血清FLT3L水平均显著降低，这进一步证实了TACE作为体内FLT3L裂解酶的相关性。考虑到FLT3和FLT3L在造血系统恶性肿瘤和干细胞动员中的作用，鉴定参与FLT3L脱落的酶可能具有重要的临床意义。
