Cellular Adhesion Molecules

Cellular adhesion molecules (CAMs) are cell surface glycoproteins involved in cell-cell and cell-matrix interactions. CAMs are critical for leukocyte adhesion to endo-thelium, transmigration, binding to target cells, and cytotoxicity. Following is a review of CAMs that have been shown to be relevant to inflammatory liver disease, and we suggest the following articles to readers: Ref. [6, 8-10].

Integrins

Resident liver cells (e.g., Kupffer cells and pit cells) as well as newly recruited monocytes, T lymphocytes and neutrophils have b1 and b2-integrins on their surface. LFA-1 (aLb2) is highly expressed on all leukocytes. By contrast, Mac-1 (aMb2) is present primarily on neutrophils, Kupffer cells, and monocytes, and to a small degree on pit cells. VLA-4 (a4b1) is expressed mainly by T cells, pit cells, and monocytes, and to some degree on Kupffer cells and under limited conditions neutrophils. The activation of integrins has been observed in situations akin to liver injury in vivo. Indeed, increased Mac-1 expression on neutrophils was observed during reperfusion after hepatic ischemia, endo-toxemia, and sepsis.

Intercellular Adhesion Molecules

Intercellular adhesion molecules (ICAM-1, -2 and -3), vascular adhesion molecule (VCAM-1), and platelet endothelial adhesion molecules-1 (PECAM-1) are also important in an inflammatory response. In the normal liver, no ICAM-1 is found on hepatocytes or stellate cells and low expression of ICAM-1 can be found on the entire hepatic endothelium and Kupffer cells. During inflammation, ICAM-1 is strongly upregulated by TNFa, IL-1ß, and IFNg on all liver cells (Table I). This induction is promptly followed by the recruitment of leukocytes into the liver, where they attach to and subsequently damage the liver cells. In normal livers there is low VCAM-1 expression on venule, arteriole, and sinusoidal endothelial cells. No constitutive or inducible VCAM-1 has been observed on hepatocytes. With exposure to TNFa or IL-1ß both Kupffer cells and endothelial cells upregulate VCAM-1 (Table I). Vascular adhesion protein (VAP)-1 is constitutively expressed on human sinusoidal endothelial cells and has been shown to mediate lymphocyte recruitment and possibly transendothelial transmigration. PECAM-1 has been shown to be important for leukocyte transendothelial migration. Studies have shown PECAM-1 to be constitutively expressed on large vessel endothelial cells but not sinusoidal endothelial cells. PECAM-1 is not inducible with inflammatory mediators (Table I).

Selectins

The selectin family includes three molecules, that is, L-, E-, and P-selectin. L-selectin is constitutively expressed on neutrophils and is shed from the cell surface during activation. Notably, this shedding coincides with Mac-1 upregula-tion on neutrophils. There are important differences in the expression of selectin adhesion molecules between vascular and sinusoidal endothelium. P-selectin is stored in secretory granules (Weibel-Palade bodies in endothelial cells). Liver sinusoidal endothelial cells do not contain WP bodies and consistent with this lack of WP bodies, sinusoidal endothe-lial cells do not express P-selectin (Table I). By contrast, under inflammatory conditions, P- and E-selectin can be strongly induced on the portal vascular endothelium (Table I). These differences may reflect a lack of requirement for selectin-mediated tethering in the low-flow environment of the sinusoid. Indeed, leukocyte recruitment to the sinusoidal area has been shown, in vivo, to occur in the absence of selectins.

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