scholarly journals Rap1 translates chemokine signals to integrin activation, cell polarization, and motility across vascular endothelium under flow

2003 ◽  
Vol 161 (2) ◽  
pp. 417-427 ◽  
Author(s):  
Mika Shimonaka ◽  
Koko Katagiri ◽  
Toshinori Nakayama ◽  
Naoya Fujita ◽  
Takashi Tsuruo ◽  
...  
Keyword(s):  
Adhesion Molecule ◽  
Leading Edge ◽  
Intercellular Adhesion ◽  
Cell Polarization ◽  
Intercellular Adhesion Molecule ◽  
Integrin Activation ◽  
Intercellular Adhesion Molecule 1 ◽  
Circulating Lymphocytes ◽  
And Migration ◽  
Cell Adhesion Molecule 1

Chemokines arrest circulating lymphocytes within the vasculature through the rapid up-regulation of leukocyte integrin adhesive activity, promoting subsequent lymphocyte transmigration. However, the key regulatory molecules regulating this process have remained elusive. Here, we demonstrate that Rap1 plays a pivotal role in chemokine-induced integrin activation and migration. Rap1 was activated by secondary lymphoid tissue chemokine (SLC; CCL21) and stromal-derived factor 1 (CXCL4) treatment in lymphocytes within seconds. Inhibition of Rap1 by Spa1, a Rap1-specific GTPase-activating protein, abrogated chemokine-stimulated lymphocyte rapid adhesion to endothelial cells under flow via intercellular adhesion molecule 1. Expression of a dominant active Rap1V12 in lymphocytes stimulated shear-resistant adhesion, robust cell migration on immobilized intercellular adhesion molecule 1 and vascular cell adhesion molecule 1, and transendothelial migration under flow. We also demonstrated that Rap1V12 expression in lymphocytes induced a polarized morphology, accompanied by the redistribution of CXCR4 and CD44 to the leading edge and uropod, respectively. Spa1 effectively suppressed this polarization after SLC treatment. This unique characteristic of Rap1 may control chemokine-induced lymphocyte extravasation.

Endothelial tetraspanin microdomains regulate leukocyte firm adhesion during extravasation

Blood ◽  
2005 ◽  
Vol 105 (7) ◽  
pp. 2852-2861 ◽  
Author(s):  
Olga Barreiro ◽  
María Yáñez-Mó ◽  
Mónica Sala-Valdés ◽  
María Dolores Gutiérrez-López ◽  
Susana Ovalle ◽  
...  
Keyword(s):  
Adhesion Molecule ◽  
Leukocyte Adhesion ◽  
Transendothelial Migration ◽  
Intercellular Adhesion ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Glutathione S Transferase ◽  
Large Extracellular Loop ◽  
And Migration ◽  
Cell Adhesion Molecule 1

AbstractTetraspanins associate with several transmembrane proteins forming microdomains involved in intercellular adhesion and migration. Here, we show that endothelial tetraspanins relocalize to the contact site with transmigrating leukocytes and associate laterally with both intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Alteration of endothelial tetraspanin microdomains by CD9–large extracellular loop (LEL)–glutathione S–transferase (GST) peptides or CD9/CD151 siRNA oligonucleotides interfered with ICAM-1 and VCAM-1 function, preventing lymphocyte transendothelial migration and increasing lymphocyte detachment under shear flow. Heterotypic intercellular adhesion mediated by VCAM-1 or ICAM-1 was augmented when expressed exogenously in the appropriate tetraspanin environment. Therefore, tetraspanin microdomains have a crucial role in the proper adhesive function of ICAM-1 and VCAM-1 during leukocyte adhesion and transendothelial migration.

Gamma Knife Irradiation Increases Cerebral Endothelial Expression of Intercellular Adhesion Molecule 1 and E-selectin

Neurosurgery ◽  
2003 ◽  
Vol 53 (1) ◽  
pp. 154-161 ◽  
Author(s):  
Christopher D. Sharp ◽  
Ajay Jawahar ◽  
April C. Warren ◽  
John W. Elrod ◽  
Anil Nanda ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Gamma Knife ◽  
Adhesion Molecule ◽  
Intercellular Adhesion ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Lactate Dehydrogenase Release ◽  
Gamma Knife Stereotactic Radiosurgery ◽  
Cell Adhesion Molecule 1 ◽  
Upper Chamber

Abstract OBJECTIVE Alterations in multiple functions of the microvasculature occur in response to gamma irradiation and are thought to contribute to radiation-induced end organ damage by inducing inflammatory responses, particularly leukocyte infiltration into the affected area. Endothelial cell adhesion molecules (ECAMs) mediate leukocyte adhesion and migration. Here, we validate a method to study the effect of Leksell gamma knife stereotactic radiosurgery on the expression of ECAMs on human cerebral endothelium at 0, 24, 48, and 72 hours after irradiation. METHODS A human brain endothelial cell line (IHEC) was cultured on 12-mm coverslips and subjected to 50 Gy of collimated gamma irradiation with the Leksell gamma knife (Elekta Instruments, Inc., Atlanta, GA). Lactate dehydrogenase release was measured at 24, 48, and 72 hours after irradiation and caspase-3 at 24, 48, 72, 96, and 120 hours. ECAM expression was measured at postirradiation intervals of 0, 24, 48, and 72 hours by cell enzyme-linked immunoabsorbent assay. We used a cell irradiator composed of two chambers. The upper chamber holds the coverslips firmly in place while they are immersed in media. The lower chamber is connected to a peristaltic pump, which pumps water into the chamber and maintains the media in the upper chamber at 37°C through convection. RESULTS None of the ECAMs tested was significantly elevated compared with the control basally. Twenty-four hours after irradiation, intercellular adhesion molecule 1 was significantly elevated on brain endothelial cells but there was no significant elevation of E-selectin. Vascular cell adhesion molecule 1 was increased slightly but not significantly and decreased at 48 hours. At 72 hours, E-selectin expression was significantly increased; intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 were not altered relative to sham controls. CONCLUSION Increased ECAM expression and lactate dehydrogenase release support the idea that the cerebral microvasculature undergoes an inflammatory response after Leksell gamma knife stereotactic radiosurgery.

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