Regulation of adhesion molecule expression and function

The adhesive nature of cells is regulated at many levels. The level of expression of adhesion molecules on the cell surface is dependent in large part on the activation status of the cell. Activation of endothelial cells with inflammatory cytokines, such as inter-leukin 1 (IL-1) and tumor necrosis factor a (TNFa), results within hours in an increase in expression of E-selectin, ICAM-1 and VCAM-1. This cytokine-induced expression of these adhesion molecules is due to transcriptional upregulation of the genes encoding these molecules. P-selectin is also expressed on activated endothelium, as well as on platelets. However, P-selectin is stored in granules, ready to be upregulated within minutes in response to stimulation. Stimulation of neutrophils with agonists such as formyl-Met-Leu-Phe (fMLP) also results in the rapid upregulation of the Mac-1 integrin due to fusion of intracellular granules containing Mac-1 molecules with the plasma membrane.

Adhesion molecules can also be rapidly lost from the cell surface. The most notable example is L-sel-ectin, which is constitutively expressed on most peripheral blood leukocytes. However, leukocyte activation can result in rapid proteolytic cleavage (shedding) of L-selectin from the cell surface. Although the protease responsible for L-selectin shedding has not been identified, the cleavage of L-selectin from the cell surface has been demonstrated to be important for leukocyte interactions with endothelium. Other adhesion molecules, including CD44, E-selectin, ICAM-1 and VCAM-1, can also be found in soluble form. The functional significance of soluble adhesion molecules is not entirely clear, bur changes in the level of expression of soluble adhesion molecules in various disease states have been noted.

Stable changes in the expression of adhesion molecules can also be observed during the process of lymphocyte differentiation. For example, when naive T cells are activated, some of the activated T cells differentiate into memory T cells. These memory T cells can be distinguished from naive T cells by differential expression of several adhesion molecules. Some adhesion molecules, such as the LFA-1 integrin, 3,-integrins and CD44, show increased expression on memory T cells, while others, such as L-selectin, show reduced expression. These differences in adhesion molecule expression on naive and memory T cells are believed to be responsible in part for the differences in naive and memory T cell recirculation in vivo. For example, uniform expression of L-selectin on naive T cells is believed to be critical for the preferential migration of naive T cells into peripheral lymph nodes via adhesion and transmigration through peripheral lymph node high endothelial venules (HEV). Differentiation of thymocytes is also characterized by discrete changes in the expression of various adhesion molecules.

The functional activity of adhesion molecules can also be regulated by cellular activation. Stimulation of leukocytes and platelets results within seconds to minutes in rapid increases in integrin-mediated adhesion that do not require changes in levels of integrins on the cell surface. Such activation of integrins from a latent cell surface form is an essential element of the multistep paradigm of leukocyte interactions with endothelium. Furthermore, the ability of T cell receptor stimulation to activate integrins in such a manner implicates this mode of regulation in enhancing T cell contact with antigen presenting cells. T Cell receptor stimulation has also been reported to increase the adhesiveness of the CD2 molecule. The intracellular mechanisms by which activation rapidly upregulates the adhesive nature of these molecules remain poorly defined.

Adhesion molecules may also be regulated by other molecules that physically associate with adhesion receptors and consequently alter adhesive activity. Integrin-mediated cell adhesion to fibronec-tin has been shown to be inhibited by expression of the uPAR, which physically associates with (B,-inte-grins as well as the Mac-1 integrin. Studies of four transmembrane-containing (TM-4) proteins (CD9, CD63 and CD81/TAPA-1) have also demonstrated an association of these proteins on the cell surface with integrins, although the functional significance of this association for integrin function remains unclear. These observations suggest that additional membrane localized proteins may be identified in the future with similar roles of enhancing or inhibiting adhesion molecule function through physical association in the plasma membrane.

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