title: Rapid and recurrent neutrophil mobilization regulated by T134, a CXCR4 peptide antagonist.
abstract: The CXCR4/stromal cell-derived factor-1 (SDF-1) axis plays important roles in development, leukocyte trafficking, HIV infection, and tumorigenesis. Its critical function in bone marrow stem cell and hematopoietic progenitor cell retention, homing and release has been well-characterized by genetic and pharmacological analyses. However, its role in neutrophil retention and release is still poorly understood. In this study, we demonstrated that T134, a peptide antagonist of human CXCR4, is also a potent antagonist of mouse CXCR4. Treatment of C57BL/6 mice with T134 resulted in a rapid and time-dependent increase of white blood cells (WBC) and neutrophils, as well as hematopoietic stem and progenitor cells in peripheral blood. Interestingly, recurrent WBC and neutrophil mobilization was achieved by repeated T134 treatment, and the T134-mediated increase and subsequent retreat of WBC and neutrophils correlated with T134 activity in the peripheral blood. Kinetic analysis revealed that T134 binding to CXCR4 did not induce any significant cell-surface receptor downregulation, indicating that T134-induced WBC and neutrophil mobilization is likely due to direct blockage of the CXCR4/SDF-1 interaction. The results from this study support an important role of CXCR4/SDF-1 axis in neutrophil retention and release in the marrow.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: Chandrasekar V
authors.initials: CV
authors.lastname: Iyer
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Evans
authors.forename: Qinyuan
authors.initials: Q
authors.lastname: Lou
authors.forename: Datian
authors.initials: D
authors.lastname: Lin
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Wayne
authors.initials: W
authors.lastname: Kohn
authors.forename: Liang Zeng
authors.initials: LZ
authors.lastname: Yan
authors.forename: Shon
authors.initials: S
authors.lastname: Pulley
authors.forename: Sheng-Bin
authors.initials: SB
authors.lastname: Peng
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects*; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003114:Colony-Forming Units Assay; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006397:Hematinics / Q000097:blood / Q000494:pharmacology*; D019650:Hematopoietic Stem Cell Mobilization; D007958:Leukocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects*; D009842:Oligopeptides / Q000097:blood / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000502:physiology; D013047:Specific Pathogen-Free Organisms
chemical_list: C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D006397:Hematinics; D009842:Oligopeptides; D019718:Receptors, CXCR4; C116978:T134 peptide