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JAM-L-mediated leukocyte adhesion to endothelial cells is regulated in cis by alpha4beta1 integrin activation.

Luissint AC, Lutz PG, Calderwood DA, Couraud PO, Bourdoulous S - J. Cell Biol. (2008)

Bottom Line: Cis dimerization of JAM-L is required to engage in heterophilic interactions with its cognate counter-receptor CAR (coxsackie and adenovirus receptor).Interestingly, JAM-L expressed on neutrophils binds CAR independently of integrin activation.However, on resting monocytes and T lymphocytes, which express the integrin VLA-4, JAM-L molecules engage in complexes with VLA-4 and mainly accumulate in their monomeric form.

View Article: PubMed Central - PubMed

Affiliation: Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Paris F-75014, France.

ABSTRACT
Junctional adhesion molecules (JAMs) are endothelial and epithelial adhesion molecules involved in the recruitment of circulating leukocytes to inflammatory sites. We show here that JAM-L, a protein related to the JAM family, is restricted to leukocytes and promotes their adhesion to endothelial cells. Cis dimerization of JAM-L is required to engage in heterophilic interactions with its cognate counter-receptor CAR (coxsackie and adenovirus receptor). Interestingly, JAM-L expressed on neutrophils binds CAR independently of integrin activation. However, on resting monocytes and T lymphocytes, which express the integrin VLA-4, JAM-L molecules engage in complexes with VLA-4 and mainly accumulate in their monomeric form. Integrin activation is required for the dissociation of JAM-L-VLA-4 complexes and the accumulation of functional JAM-L dimers, which indicates that the leukocyte integrin VLA-4 controls JAM-L function in cis by controlling its dimerization state. This provides a mechanism through which VLA-4 and JAM-L functions are coordinately regulated, allowing JAM-L to strengthen integrin-dependent adhesion of leukocytes to endothelial cells.

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JAM-L expression is restricted to neutrophils, monocytes, and memory T cells. (A) Neutrophils, monocytes, and T lymphocytes freshly isolated from human peripheral blood and HBMECs stained with anti–JAM-L and analyzed by flow cytometry. Gray areas represent staining with secondary antibody alone. (B) Freshly isolated human T lymphocytes stained were with antibodies directed against the molecules indicated, fixed, and analyzed by flow cytometry. Lines demarcate the threshold for positive staining for both markers.
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fig1: JAM-L expression is restricted to neutrophils, monocytes, and memory T cells. (A) Neutrophils, monocytes, and T lymphocytes freshly isolated from human peripheral blood and HBMECs stained with anti–JAM-L and analyzed by flow cytometry. Gray areas represent staining with secondary antibody alone. (B) Freshly isolated human T lymphocytes stained were with antibodies directed against the molecules indicated, fixed, and analyzed by flow cytometry. Lines demarcate the threshold for positive staining for both markers.

Mentions: We previously identified JAM-L as a novel protein with homology to members of the JAM family. JAM-L mRNA was up-regulated in myeloid leukemia cells induced to differentiate through the granulocytic and monocytic pathways, and was expressed in normal hematopoietic cells, including neutrophils, monocytes, and lymphocytes (Moog-Lutz et al., 2003). Using anti–human JAM-L antibodies, we investigated JAM-L expression in freshly isolated human leukocytes and in cultured endothelial or epithelial cells. Consistent with the presence of JAM-L mRNA in leukocytes, JAM-L protein expression was detected at the surface of neutrophils, monocytes, and, to a lesser extent, human T lymphocytes (Fig. 1 A). However, JAM-L expression was not detected on human CD34+ hematopoietic stem cells and progenitors freshly isolated from umbilical cord blood (unpublished data). In addition, neither JAM-L protein (Fig. 1 A) nor mRNA expression (not depicted) were detected in a human bone marrow microvascular endothelial cell line; nor was it detected in endothelial or epithelial cells of different origins (primary cultures of human umbilical vein endothelial cells, saphenous vein endothelial cells, and dermal microvascular endothelial cells, as well as in the brain microvessel endothelial cell line hCMEC/D3 or the epithelial cells lines T84 and Caco-2; not depicted), which strongly suggests that, unlike any other JAMs and related molecules, human JAM-L expression is restricted to mature leukocytes.


JAM-L-mediated leukocyte adhesion to endothelial cells is regulated in cis by alpha4beta1 integrin activation.

Luissint AC, Lutz PG, Calderwood DA, Couraud PO, Bourdoulous S - J. Cell Biol. (2008)

JAM-L expression is restricted to neutrophils, monocytes, and memory T cells. (A) Neutrophils, monocytes, and T lymphocytes freshly isolated from human peripheral blood and HBMECs stained with anti–JAM-L and analyzed by flow cytometry. Gray areas represent staining with secondary antibody alone. (B) Freshly isolated human T lymphocytes stained were with antibodies directed against the molecules indicated, fixed, and analyzed by flow cytometry. Lines demarcate the threshold for positive staining for both markers.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2600739&req=5

fig1: JAM-L expression is restricted to neutrophils, monocytes, and memory T cells. (A) Neutrophils, monocytes, and T lymphocytes freshly isolated from human peripheral blood and HBMECs stained with anti–JAM-L and analyzed by flow cytometry. Gray areas represent staining with secondary antibody alone. (B) Freshly isolated human T lymphocytes stained were with antibodies directed against the molecules indicated, fixed, and analyzed by flow cytometry. Lines demarcate the threshold for positive staining for both markers.
Mentions: We previously identified JAM-L as a novel protein with homology to members of the JAM family. JAM-L mRNA was up-regulated in myeloid leukemia cells induced to differentiate through the granulocytic and monocytic pathways, and was expressed in normal hematopoietic cells, including neutrophils, monocytes, and lymphocytes (Moog-Lutz et al., 2003). Using anti–human JAM-L antibodies, we investigated JAM-L expression in freshly isolated human leukocytes and in cultured endothelial or epithelial cells. Consistent with the presence of JAM-L mRNA in leukocytes, JAM-L protein expression was detected at the surface of neutrophils, monocytes, and, to a lesser extent, human T lymphocytes (Fig. 1 A). However, JAM-L expression was not detected on human CD34+ hematopoietic stem cells and progenitors freshly isolated from umbilical cord blood (unpublished data). In addition, neither JAM-L protein (Fig. 1 A) nor mRNA expression (not depicted) were detected in a human bone marrow microvascular endothelial cell line; nor was it detected in endothelial or epithelial cells of different origins (primary cultures of human umbilical vein endothelial cells, saphenous vein endothelial cells, and dermal microvascular endothelial cells, as well as in the brain microvessel endothelial cell line hCMEC/D3 or the epithelial cells lines T84 and Caco-2; not depicted), which strongly suggests that, unlike any other JAMs and related molecules, human JAM-L expression is restricted to mature leukocytes.

Bottom Line: Cis dimerization of JAM-L is required to engage in heterophilic interactions with its cognate counter-receptor CAR (coxsackie and adenovirus receptor).Interestingly, JAM-L expressed on neutrophils binds CAR independently of integrin activation.However, on resting monocytes and T lymphocytes, which express the integrin VLA-4, JAM-L molecules engage in complexes with VLA-4 and mainly accumulate in their monomeric form.

View Article: PubMed Central - PubMed

Affiliation: Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Paris F-75014, France.

ABSTRACT
Junctional adhesion molecules (JAMs) are endothelial and epithelial adhesion molecules involved in the recruitment of circulating leukocytes to inflammatory sites. We show here that JAM-L, a protein related to the JAM family, is restricted to leukocytes and promotes their adhesion to endothelial cells. Cis dimerization of JAM-L is required to engage in heterophilic interactions with its cognate counter-receptor CAR (coxsackie and adenovirus receptor). Interestingly, JAM-L expressed on neutrophils binds CAR independently of integrin activation. However, on resting monocytes and T lymphocytes, which express the integrin VLA-4, JAM-L molecules engage in complexes with VLA-4 and mainly accumulate in their monomeric form. Integrin activation is required for the dissociation of JAM-L-VLA-4 complexes and the accumulation of functional JAM-L dimers, which indicates that the leukocyte integrin VLA-4 controls JAM-L function in cis by controlling its dimerization state. This provides a mechanism through which VLA-4 and JAM-L functions are coordinately regulated, allowing JAM-L to strengthen integrin-dependent adhesion of leukocytes to endothelial cells.

Show MeSH
Related in: MedlinePlus