Antibody-assisted enhancement of biological activities of CXCL14 in human monocytic leukemia-derived THP-1 cells and high fat diet-induced obese mice.
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')(2) fraction, 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.
Tanegashima
Kosuke
K
The Tokyo Metropolitan Institute of Medical Science, Tokyo Metropolitan Organization for Medical Research, Tokyo, Japan.
Suzuki
Kenji
K
Nakayama
Yuki
Y
Hara
Takahiko
T
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019743:Chemokines, CXC / Q000819:agonists* / Q000276:immunology* / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D004036:Diet, Atherogenic; D004041:Dietary Fats / Q000494:pharmacology; D005260:Female; D018149:Glucose Intolerance / Q000139:chemically induced; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D007948:Leukemia, Monocytic, Acute / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D011485:Protein Binding / Q000187:drug effects
D000911:Antibodies, Monoclonal; C118056:CXCL14 protein, human; D019743:Chemokines, CXC; D004041:Dietary Fats