The role of very late antigen-1 in immune-mediated inflammation

The alpha1beta1 integrin. also known as "very late antigen" (VLA)-I, is normally expressed on mesenchymal cells, some epithelial cells, activated T cells, and macrophages, and interacts, via the 1-domain of the extracellular domain of the alpha1 Subunit, with collagen molecules in the extracellular matrix (ECM). By "outside-in" transmembranal signaling to the interior of the cell, it mediates adhesion, Migration, proliferation. remodeling of the ECM, and cytokine secretion by endothelial cells, mesangial cells, fibroblasts, and immunocytes. Importantly, its expressions and functions are enhanced by inflammatory cytokines including interferon (IFN)-gamma and tumor necrosis factor (TNF)alpha. thus augmenting angiogenesis and fibrosis linked, in particular, to inflammation. Moreover, within the immune system, VLA-1 marks effector memory CD4+ and CD8+ T cells that are retained in extralymphatic tissues by interactions of the integrin with collagen and produce high levels of IFN-gamma. Thus, immune-mediated inflammation in vivo is inhibited by blockade of the VLA-1-collagen interaction in experimental animal models of arthritis, colitis, nephritis, and graft versus host disease (GVHD), suggesting that inhibiting the interaction of the alpha1 I-domain with its ligands or modulating "outside-in" signaling by VLA-1 would be a useful approach in the human diseases simulated by these experimental models. (C)2004 Elsevier Inc. All rights reserved.