Publication Date

2011-04-07

Availability

Open access

Embargo Period

2011-04-07

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Physiology and Biophysics (Medicine)

Date of Defense

2010-11-22

First Committee Member

Vincent T. Moy

Second Committee Member

Wolfgang Nonner

Third Committee Member

Nirupa Chaudhari

Fourth Committee Member

Vance Lemmon

Fifth Committee Member

Xiaohui Zhang

Abstract

The chemokine, Monocyte Chemoattractant Protein (MCP-1), enhances integrin mediated monocyte adhesion to the vascular endothelium during inflammation. In this study, we demonstrate that MCP-1 promotes rapid sub-second adhesion of THP-1 cells to Vascular Cell Adhesion Molecule-1 (VCAM-1), but not to Intercellular Cell Adhesion Molecule-1 (ICAM-1). MCP-1 activates membrane tethered Very Late Antigen 4 (VLA-4, α4β1), but not necessarily cytoskeleton anchored VLA-4. Activated tethered VLA-4 bonds tremendously increased the period of time monocytes remain bound from hundreds of milliseconds to several seconds and also increased the distance over which immunologic surveillance occurs from several microns up to 20 microns along the endothelium. Lastly at the single molecule level, MCP-1 stimulated tethered VLA-4 bonds exhibit increased resistance to pulling force. In conclusion MCP-1 increased tethered VLA-4 bond resistance to force providing a mechanism for monocyte recruitment to the endothelium.

Keywords

Atomic Force Microscope; Single Molecule Force Spectroscopy; Integrin; Cellular Adhesion; VLA-4; VCAM-1

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