Cell Adhesion Molecules (CAMs) are proteins located on the cell surface involved with the binding with other cells or with the extracellular matrix (ECM) in the process called cell adhesion.
These proteins are typically transmembrane receptors and are composed of three domains: an intracellular domain that interacts with the cytoskeleton, a transmembrane domain and an extracellular domain that interacts either with other CAMs of the same kind (homophilic binding) or with other CAMs or the extracellular matrix (heterophilic binding).
Families of CAMs
Most of the CAMs belong to 4 protein families: Ig (immunoglobulin) superfamily (IgSF CAMs), the integrins, the cadherins and the selectins.
Immunoglobulin SuperFamily CAMs (IgSF CAMs) are either homophilic or heterophilic and bind integrins or different IgSF CAMs. Here is a list of some molecules of this family:
The selectins are a family of heterophilic CAMs that bind fucosylated carbohydrates, e.g. mucins? . They are dependent on divalent cations. The most important family members are E-selectins (endothelial), L-selectins (leukocyte) and P-selectins (platelet). An example of a member of this family is the P-selectin glycoprotein ligand-1 (PSGL-1).
The integrins are a family of heterophilic CAMs that bind IgSF CAMs or the extracellular matrix. They are heterodimers, consisting in two non-covalently linked subunits, called alpha and beta. 24 different alpha subunits are known that can link in many different combinations with the 9 different beta subunits, however not all combinations are observed.
The cadherins are a family of homophilic CAMs, Calcium dependant. The most important members of this family are E-cadherins (epithelial), P-cadherins (placental) and N-cadherins (neural).
In diabetes, glycation, tissue oxidation and endothelial function are all abnormal and predisposing to microvascular complications but interrelationships are complex with glycation appearing most direct.
Levels of soluble adhesion molecules vWf, E-selectin and VCAM are raised in Type 2 diabetes mellitus. In diabetic humans, elevated plasma [von Willebrand Factor (vWF)]? has been interpreted as an indication of endothelial damage.
Endothelial activation and acute-phase reaction correlate with insulin resistance and obesity in type 2 diabetic patients obesity may induce endothelial activation or increased shedding of cell surface E-selectin that leads to subsequent increase in soluble E-selectin levels. High serum concentrations of E-selectin closely correlate with increased total fat volume.
Pharmacognacy of adhesion antagonism
- Integrin anto-agonist: Crude ethanolic extract of the anti-rheumatic herbal drug gravel root (rhizome of Eupatorium purpureum), was identified as a potent inhibitor of ICAM-1 and some beta 1 and beta 2 integrin-mediated cell adhesions. “It appears that it has therapeutic potential for diseases where integrin adhesion molecules play a significant role.” () The active principle of gravel root has now been isolated and identified as Cistifolin (5-acetyl-6-hydroxy-2,3-dihydro-cis-2-isopropenyl-3- tiglinoyloxybenzofuran). Cistofolin appears to alter T cell production of the macrophage-attracting chemokines CCL3 and CCL4 which appear to alter expression of ICAM-1. cistifolin inhibits the Mac-1 (CD11b/CD18)-dependent monocyte adhesion to fibrinogen in a concentration-dependent manner
- Feverfew (parthenolide) also inhibits the expression of intercellular adhesion molecule-1 (ICAM-1) induced by the cytokines IL-1 and other integrin-mediated leucocyte adhesions.
- During selenium supplementation a significant decrease in molecules VCAM-1, E-selectin (after 3 months) and P-selectins and ICAM-1 (after 6 months) were observed. After 3 months of selenium supplementation we noticed a significant decrease in VCAM-1 and P-selectin expressions and after 6 months the level of VCAM-1 decreased. “Our data demonstrate that selenium is able to affect the adhesion molecules expressions that are crucial in the inflammatory process.” Significant increase in VCAM-1, P- and E-selectins expression in the group of low-selenium asthmatics in comparison with the control group.
- Astragalus membranosus, also decreases CAM expression, which is interesting in light of the fact that Astragalus accumulates selenium and can cause intoxication when grazed.
- Carotenes have diverse effects on soluable endothelial adhesion molecules. Beta carotene seems decrease some adhesion receptors and increase others. Carotenoids decrease E-selectin and ICAM.()
- Soy protein diet significantly improves plasma lipid profile in patients with hypercholesterolemia. Furthermore, the endothelial function also improves with soy protein diet. () Genestein inhibits tyrosine kinases required for ICAM and E-selectin upregulation.
Oligomeric proanthocyanidins (OPC's)
- The main constituents of Crataegus are flavonoids, triterpene saponins and a few cardioactive amines; however, the primary cardiovascular protective activity of the plant is its flavonoid content, particularly the oligomeric proanthocyanidins (OPC's). The potent inhibitory effect of low concentrations of OPCs on agonist-induced VCAM-1 expression suggests therapeutic potential in inflammatory conditions and other pathologies involving altered expression of VCAM- 1. ()
- “In conclusion, isolated hypercholesterolemia both increased circulating sVCAM-1 and reduced Nitric Oxide metabolite concentrations. Vitamin E supplementation counteracts these alterations, thus representing a potential tool for endothelial protection in hypercholesterolemic patients.” ()
Red Rice Yeast
Statins reduce E-selectin and ICAM. Red Rice Yeast (dihydromonacolin, monacolin I-VI, monacolin M, Monacolin K [very low]) may be an effective strategy in the management of diabetic complications.
The anti-inflammatory action of methotrexate is not mediated by lymphocyte apoptosis, but by the suppression of activation and adhesion molecules
Clin Immunol. 2005 Feb ;114:154-63
Andrew Johnston, Johann Eli Gudjonsson, Hekla Sigmundsdottir, Björn Runar Ludviksson, Helgi Valdimarsson
Low-dose methotrexate (MTX) is an established and highly effective treatment for severe psoriasis and rheumatoid arthritis; however, its mechanism of action remains unclear. We investigated the effects of low-dose MTX on antigen-stimulated peripheral blood mononuclear cells and explored through which cellular pathways these effects are mediated. We show that MTX caused a dose-dependent suppression of T cell activation and adhesion molecule expression, and this was not due to lymphocyte apoptosis. The suppression of intercellular adhesion molecule (ICAM)-1 was adenosine and folate-dependent, while MTX suppression of the skin-homing cutaneous lymphocyte-associated antigen (CLA) was adenosine-independent. The effect of MTX on CLA, but not ICAM-1, required the constant presence of MTX in cultures. Thus, the suppression of T cell activation and T cell adhesion molecule expression, rather than apoptosis, mediated in part by adenosine or polyglutamated MTX or both, are important mechanisms in the anti-inflammatory action of MTX.
The role of adhesion molecules in atherosclerosis.
Crit Rev Clin Lab Sci. 1998 Dec;35(6):573-602. Chia MC.
- The progression of atherosclerosis is currently believed to involve the interaction of monocytes with the vascular endothelium. Within the last decade, the cell-surface proteins thought to control these interactions have been investigated. This review seeks to describe the nature of these interactions through what are known as adhesion molecules and their role in atherogenesis. It begins with the stages of atherogenesis from the movement of the monocyte to the endothelium, followed by the migration of smooth muscle cells from the media to the intima, and subsequently to the later stages of fibrofatty plaque formation and potential complications due to thrombosis and/or plaque fissure and embolism. The different structural classifications of the adhesion molecules, such as integrins, cadherins, selectins, and members of the immunoglobulin gene superfamily, are outlined, and interaction of binding domains are highlighted. The vascular endothelium and the basic role of adhesion molecules in dysfunction are considered. Discussion of the role of adhesion molecules in atherogenesis focuses on interactions of the endothelium, monocytes, and leukocytes, as well as the influences of cytokines, oxidized low-density lipoproteins, and genetic determinants. Finally, epidemiological risk factors associated with atherosclerosis such as hypertension and dyslipidemia are considered in light of their effects on adhesion molecule expression.