The Chemokine Stromal Cell-Derived Factor-1α Modulates α4β7 Integrin-Mediated Lymphocyte Adhesion to Mucosal Addressin Cell Adhesion Molecule-1 and Fibronectin

Abstract

The interaction between the integrin α4β7 and its ligand, mucosal addressin cell adhesion molecule-1, on high endothelial venules represents a key adhesion event during lymphocyte homing to secondary lymphoid tissue. Stromal cell-derived factor-1α (SDF-1α) is a chemokine that attracts T and B lymphocytes and has been hypothesized to be involved in lymphocyte homing. In this work we show that α4β7-mediated adhesion of CD4+ T lymphocytes and the RPMI 8866 cell line to mucosal addressin cell adhesion molecule-1 was up-regulated by SDF-1α in both static adhesion and cell detachment under shear stress assays. Both naive and memory phenotype CD4+ T cells were targets of SDF-1α-triggered increased adhesion. In addition, SDF-1α augmented α4β7-dependent adhesion of RPMI 8866 cells to connecting segment-1 of fibronectin. While pertussis toxin totally blocked chemotaxis of CD4+ and RPMI 8866 cells to SDF-1α, enhanced α4β7-dependent adhesion triggered by this chemokine was partially inhibited, indicating the participation of Gαi-dependent as well as Gαi-independent signaling. Accordingly, we show that SDF-1α induced a rapid and transient association between its receptor CXCR4 and Gαi, whereas association of pertussis toxin-insensitive Gα13 with CXCR4 was slower and of a lesser extent. SDF-1α also activated the small GTPases RhoA and Rac1, and inhibition of RhoA activation reduced the up-regulation of α4β7-mediated lymphocyte adhesion in response to SDF-1α, suggesting that activation of RhoA could play an important role in the enhanced adhesion. These data indicate that up-regulation by SDF-1α of lymphocyte adhesion mediated by α4β7 could contribute to lymphocyte homing to secondary lymphoid tissues.

CXCR4 chemokine receptor and integrin signaling co-operate in mediating adhesion and chemoresistance in small cell lung cancer (SCLC) cells

“…These data indicate that also Gai-independent signaling must be involved in CXCL12 enhanced adhesion. In accordance with our findings Wright et al (2002) demonstrated in a study on lymphocytes that PT completely blocked chemotaxis, but the a4b7-dependent adhesion of B and T lymphocytes triggered by CXCL12 was only partially inhibited by PT. In the same work Wright et al reported that inhibition of RhoA activation reduced the upregulation of a4b7-dependent adhesion, suggesting that activation of RhoA is an important step in the signaling leading to increased adhesion.…”

Lsc activity is controlled by oligomerization and regulates integrin adhesion

“…RhoA has been shown to facilitate both the establishment (Giagulli et al, 2004;Laudanna et al, 1996;Vielkind et al, 2005;Wright et al, 2002) and resolution (Alblas et al, 2001;Smith et al, 2003;Worthylake et al, 2001;Yoshinaga-Ohara et al, 2002) of integrinmediated adhesive events. Whether RhoA promotes adhesion or resolution of adhesion likely depends on which of the numerous signaling pathways that lead to RhoA activation is active.…”

“…Because Lsc is a RhoA-specific GEF and RhoA has been implicated in integrinmediated adhesion (Giagulli et al, 2004;Laudanna et al, 1996;Vielkind et al, 2005;Wright et al, 2002) and resolution of adhesion (Alblas et al, 2001;Liu et al, 2002;Smith et al, 2003;Worthylake et al, 2001;Yoshinaga-Ohara et al, 2002), we next assessed how Lsc oligomerization and functional activity correlated with cell morphology and adhesion to integrin ligands. Figure 4A shows that parental and A20 transfectants exhibit a round nonstellate morphology when incubated on BSA-coated substrate.…”

Stem cells: novel players in the treatment of erectile dysfunction

“…[58][59][60][61][62][63] Rolling and firm adhesion is followed by transendothelial migration across the physical endothelium/extracellular matrix barrier.…”