Very late antigen

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. 

Lin K-C, Castro AC (1998) Very late antigen 4 (VLA4) antagonists as anti-inflammatory agents. Curr Opin Chem Biol 2 453—457... 

A 3D model of the fibrinogen-derived (very late antigen-4, VLA-4) inhibitor 4-[N -(2-methylphenyl)ureido]phenylacetyl-Leu-Asp-Val was derived from the X-ray structure of the related integrin-binding region of the vascular cell adhesion molecule-1 (VCAM-1). A 3D pharmacophore was generated with the program Catalyst, and a 3D search was performed in 8624 molecules from... 

Note LFA-1 = lymphocyte function-associated molecule, VLA-4 = very late antigen 4 see text for details. 

Other adhesion receptors that are structurally and functionally related include the receptors for fibronectin, vitronectin, platelet glycoproteins 13b and Ilia and the VLA (very-late antigen) series. All molecules involved in adhesion recognise the RGD motif and require the divalent cations Ca2+ and Mg2+ for binding. All are dimers of glycosylated proteins with relative molecular masses 95-190 kDa. There is also some sequence homology between the /J-chain (CD18) and one chain of the fibronectin receptor. 

SOD ha T cell Tc TcR TGA Th TLC TMP/SMX TNF Ts TX U V domain VLA Ml H m superoxide dismutase half-life thymus-derived lymphocyte cytotoxic T cell T-cell receptor thymine-guanine-adenine T helper cell thin layer chromatography trimethoprim/sulphamethazole tumour necrosis factor T suppressor cell thromboxane unit variable domain very-late antigen microlitre (10 6 litre) micrometre (10"6 metre)... 

Takada Y Strominger JL, Hemler ME. The very late antigen family of heterodimers is part of a superfamily of molecules in adhesion and embryogenesis. Proc Natl Acad Sci USA 1987 84( 10) 3239 3243. 

Hemler ME, Crouse C, Takada Y SonnenbergA. Multiple very late antigen (VLA) heterodimers on platelets. Evidence for distinct VLA-2, VLA-5 (fibrinogen receptor) and VLA-6 structures. J Biol Chem 1988 263(16) 7660-7665. 

VCAM-1 (vascular cell adhesion molecule) this binds to VLA-4 (very late antigen)... 

Okigami H, Takeshita K, Tajimi M, Komura H, Albers M, Lehmann TE, Rolle T, Bacon KB. Inhibition of eosinophilia in vivo by a small molecule inhibitor of very late antigen (VLA)-4. Eur. J. Pharmacol. 2007 559 202-9... 

Dasgupta S, Jana M, Liu X, Pahan K (2003) Role of very-late antigen-4 (VLA-4) in myelin basic protein-primed T cell contact-induced expression of proinflammatory cytokines in microglial cells. J Biol Chem 278 22424-22431. 

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]. 

Enders U, Lobb R, Pepinsky RB, Hartung HP, Toyka KV, Gold R (1998) The role of the very late antigen and its counterligand vascular cell adhesion molecule-1 in the pathogenesis of experimental autoimmune neuritis of the Lewis rat. Brain 121 1257-1266. 

Walsh, G.M., Mermod, J.J., Hartnell, A., Kay, A.B. and Wardlaw, A.J. (1991a). Human eosinophil, but not neutrophil, adherence to IL-1-stimulated human umbilical vascular endothelial cells is alpha 4 beta 1 (very late antigen-4) dependent. J. Immunol. 146, 3419-3423. 

Allen AR, McHale J, Smith J, Cook HT, Karkar A, et al. 1999. Endothelial expression of VCAM-1 in experimental crescentic nephritis and effect of antibodies to very late antigen-4 or VCAM-1 on glomerular injury. J Immunol. 162 5519— 27... 

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. 

VONDERHEIDE, R.H. SPRINGER, T.A. (1992) Lymphocyte adhesion through the very late antigen 4 evidence for a novel binding site in the alternatively spliced domain of VCAM-1 and an additional a4 integrin counter receptor on stimulated endothelium. Journal of Experimental Medicine, 175, 1433-1442. 

Tilley JW (2008) Very late antigen-4 integrin antagonists. Expert Opin Ther Patents 18 841-859... 

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... 

SHR spontaneously hypertensive rats VLA very late antigen... 

DupPa C, Couffinhal T, Dufourcq P, Lianas B, Moreau C, Bonnet J (1997) The integrin very late antigen-4 is expressed in human smooth muscle cell. Circ Res 80 159-169... 

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