Antibody-assisted enhancement of biological activities of CXCL14 in human monocytic leukemia-derived THP-1 cells and high fat diet-induced obese mice.
Antibody-assisted enhancement of biological activities of CXCL14 in human monocytic leukemia-derived THP-1 cells and high fat diet-induced obese mice.
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DOI：
10.1016/j.yexcr.2010.01.016
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发表时间：
2010-04
影响因子：
3.7
通讯作者：
Kosuke Tanegashima;Kenji Suzuki;Y. Nakayama;T. Hara
中科院分区：
文献类型：
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作者：
Kosuke Tanegashima;Kenji Suzuki;Y. Nakayama;T. Hara
CXCL 14是一种CXC型趋化因子，作用于组织巨噬细胞、未成熟树突状细胞、自然杀伤细胞和上皮肿瘤细胞。它还通过减弱胰岛素活性在肥胖小鼠中作为代谢调节剂。与其他CXC趋化因子相比，CXCL 14如何激活其细胞表面上的假定受体以及它是否诱导趋化作用仍有待澄清。这主要是由于目前可用的CXCL 14生物测定的灵敏度不足。在这项研究中，我们发现，抗CXCL 14的单克隆抗体，MAB 730，显着增强CXCL 14在人单核细胞白血病衍生的THP-1细胞和未成熟的树突状细胞的活性。MAB 730以不同的剂量要求增强CXCL 14介导的趋化性和趋化作用。趋化诱导活性保留在MAB 730 F（ab '）2部分中，但不在Fab部分中，这意味着配体二聚化参与MAB 730辅助的CXCL 14活性增强。此外，MAB 730在抑制CXCL 14与THP-1细胞上的低亲和力受体结合方面比肝素更有效。最后，将MAB 730抗体体内给予高脂肪饮食诱导的肥胖小鼠增加了全身胰岛素抵抗和葡萄糖耐受不良。MAB 730的这些独特性质将有助于阐明CXCL 14引起的细胞应答的分子机制。
CXCL14 is a CXC-type chemokine acting on tissue macrophages, immature dendritic cells, natural killer cells, and epithelial tumor cells. It also serves as a metabolic regulator in obese mice by blunting insulin activity. In contrast to other CXC chemokines, it remains to be clarified how CXCL14 activates its putative receptors on the cell surface and whether it induces chemokinesis. This is mainly due to the insufficient sensitivity of currently available bioassays for CXCL14. In this study, we found that the anti-CXCL14 monoclonal antibody, MAB730, remarkably enhances the activities of CXCL14 in human monocytic leukemia-derived THP-1 cells and immature dendritic cells. MAB730 augmented CXCL14-mediated chemotaxis and chemokinesis with distinct dose requirement. Chemotaxis inducing activity was retained in the MAB730 F(ab')2fraction, but not in the Fab fraction, implying that ligand dimerization is involved in the MAB730-assisted enhancement of CXCL14 activity. In addition, MAB730 was more efficient than heparin at inhibiting CXCL14 binding to low affinity receptors on THP-1 cells. Finally, in vivo administration of MAB730 antibody into high fat diet-induced obese mice increased whole body insulin resistance and glucose intolerance. These unique properties of MAB730 will be useful for elucidating the molecular mechanism of cellular responses elicited by CXCL14.