Very late antigen activator

The largest numbers of integrins are members of the (31 integrins, also known as the very late antigen (VLA) subfamily because of its late appearance after activation. There are at least seven receptors characterized from this subfamily, each with different ligand specificity. Among the most studied include the 04(31 and a5 31 receptors. The leukocyte integrin a4 31 is a cell adhesion receptor that is predominantly expressed on lymphocytes, monocytes and eosinophils. 

Integrins themselves are found on nearly all cells and mediate several physiological responses, such as cell-cell and cell-matrix interactions. Three families of integrins, each family with a common beta subunit in combination with distinct alpha subunits, have been recognized. The beta 1 family, also called very late lymphocyte-activation antigen or VLA, has receptors mediating extracellular matrix interactions with molecules such as collagen, laminin, and fibronectin. Naturally, platelets contain many of the receptors of the beta 1 family. 

Marui et al. clarified the relation between oxidative stress in the arterial wall (in particular, the endothelium) and the development of the inflammatory response [19,25]. Expression of VCAM-1 by hmnan endothelial cells stimulated by cytokines such as interleukin-1 (IL-1) is mediated by redox-sensitive control mechanisms [25]. The redox-sensitive nature of this gene regulation was determined by the use of antioxidants that are active intracellularly. It was reported that the antioxidant pyrolidine dithiocarbamate (PDTC) inhibited the IL-1-induced endothelial expression of mRNA for VCAM-1 and was as effective as a monoclonal antibody against the VCAM-1 counterligand very late antigen-4 (VLA-4) in inhibiting binding of Molt-4 cells, which express VLA-4 [25]. 

The Pi integrins are also known as the very late antigen (VLA) subfamily because they were first identified on lymphocytes several days after activation.31 At present there are six members, all of which bind to proteins of the extracellular matrix (see Table 6.1). Unlike the other molecules, VLA-4 (CD49d) is found on the majority of unstimulated T lymphocytes, its expression being higher on memory than naive cells.32 It contributes to T-cell adhesion to inflamed endothelium by interacting with VCAM-1 and, as we shall see later, VLA-4 facilitates T-cell infiltration across the BBB in EAE. 

Muro F, Iimura S, Sugimoto Y et al (2009) Discovery of trans-4-[l-[[2,5-dichloro-4-(l-methyl-3-indolylcarboxamide)phenyl]acetyl]-(4 S)-methoxy-(2 S)-pyrrolidinylmethoxy] cyclo-hexanecarboxylic acid an orally active, selective very late antigen-4 antagonist. J Med Chem 52 7974-7992... 

Red wine consumption in humans reduces TNF-a-induced adhesion of monocytes to endothelial cells ex vivo and is associated with the downregulation of monocyte adhesion molecules, in particular very late activation antigen-4 (VLA-4). Estruch et al. reported similar findings for VLA-4 and also showed that levels of MCP-1, VCAM-1, and ICAM-1 were decreased after red wine consumption. Interestingly, control studies with gin revealed no effect... 

Nakayama, H., Sano, H., Nishimura, T., Yoshidi, S., and Iwamoto, I. (1994) Role of vascular cell adhesion molecule 1/very late activation antigen 4 and intercellular adhesion molecule 1/lymphocyte function-associated antigen 1 interactions in antigen-induced eosinophil and T cell recruitment into the tissue. J. Exp. Med. 179,1145-1154. 

In addition, vascular endothelial cells become activated in patients with sickle cell disease, resulting in the exposure of adhesion molecules, in particular, vascular cell adhesion molecule 1 (VCAM-1), which is present on the surface of the vascular endothelium in sickle cell disease. An integrin on the red cell, designated very late activation antigen 4, binds with... 

Mechanisms of eosinophil adherence to cultured vascular endothelial cells. Eosinophils bind to the cytokine-induced ligand vascular cell adhesion molecule-1 via the very late activation antigen-4 integrin receptor. J. Clin. Invest. 88, 20-26. 

PRETOLANI, M RUFFIE, C LAPA E SILVA, J.R., JOSEPH, D LOBB, R.R. VARGAFTIG, B.B. (1994) Antibody to very late activation antigen 4 prevents antigen induced bronchial hyperreactivity and cellular infiltration in the guinea pig airways. Journal of Experimental Medicine, 180, 795-805. 

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