The chemokine stromal cell-derived factor-1 alpha modulates alpha 4 beta 7 integrin-mediated lymphocyte adhesion to mucosal addressin cell adhesion molecule-1 and fibronectin.
The interaction between the integrin alpha(4)beta(7) 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-1alpha (SDF-1alpha) 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 alpha(4)beta(7)-mediated adhesion of CD4(+) T lymphocytes and the RPMI 8866 cell line to mucosal addressin cell adhesion molecule-1 was up-regulated by SDF-1alpha in both static adhesion and cell detachment under shear stress assays. Both naive and memory phenotype CD4(+) T cells were targets of SDF-1alpha-triggered increased adhesion. In addition, SDF-1alpha augmented alpha(4)beta(7)-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-1alpha, enhanced alpha(4)beta(7)-dependent adhesion triggered by this chemokine was partially inhibited, indicating the participation of Galpha(i)-dependent as well as Galpha(i)-independent signaling. Accordingly, we show that SDF-1alpha induced a rapid and transient association between its receptor CXCR4 and Galpha(i), whereas association of pertussis toxin-insensitive Galpha(13) with CXCR4 was slower and of a lesser extent. SDF-1alpha also activated the small GTPases RhoA and Rac1, and inhibition of RhoA activation reduced the up-regulation of alpha(4)beta(7)-mediated lymphocyte adhesion in response to SDF-1alpha, suggesting that activation of RhoA could play an important role in the enhanced adhesion. These data indicate that up-regulation by SDF-1alpha of lymphocyte adhesion mediated by alpha(4)beta(7) could contribute to lymphocyte homing to secondary lymphoid tissues.
Wright
Natalia
N
Department of Immunology, Centro de Investigaciones Biológicas, Velázquez 144, 28006 Madrid, Spain.
Hidalgo
Andrés
A
Rodríguez-Frade
José Miguel
JM
Soriano
Silvia F
SF
Mellado
Mario
M
Parmo-Cabañas
Marisa
M
Briskin
Michael J
MJ
Teixidó
Joaquin
J
D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000502:physiology; D002448:Cell Adhesion / Q000276:immunology; D015815:Cell Adhesion Molecules; D002461:Cell Line, Transformed; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000502:physiology*; D005353:Fibronectins / Q000378:metabolism*; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism*; D007156:Immunologic Memory; D016023:Integrins / Q000502:physiology*; D007399:Interphase / Q000276:immunology; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D016131:Lymphocyte Subsets / Q000378:metabolism / Q000502:physiology*; D009088:Mucoproteins / Q000378:metabolism*; D015854:Up-Regulation / Q000276:immunology
C515255:CXCL12 protein, human; D015815:Cell Adhesion Molecules; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D005353:Fibronectins; D007136:Immunoglobulins; D016023:Integrins; C504265:MADCAM1 protein, human; D009088:Mucoproteins; C071777:integrin alpha4beta7