Adhesion molecule

Chothia, C. Jones, E.Y. The molecular structure of cell adhesion molecules. Annu. Rev. Biochem. 66 823-862, 1997. 

Intercellular adhesion molecule-1, 128 Interfacial inhibition, 159 Intrinsic activity, 44-46 Intrinsic efficacy, 9, 45, 115 Inverse agonism, 49, 108 Inverse agonists... 

Table appendix Adhesion Molecules Anti-integrins... 

The basement membrane is a structure that supports overlying epithelial or endothelial cells. The primary fimction of the basement membrane is to anchor down the epithelium to its loose connective tissue underneath. This is achieved by cell-matrix adhesions through cell adhesion molecules. 

Adhesion molecule inhibitors Intracellular signalling targets (eg SMADs)... 

Frequently, the EAR is followed by a late phase response 4-6 h later and it is caused by the pulmonary sequestration of eosinophils, neutrophils, mast cells, and T-lymphocytes. This leukocyte recruitment depends on mast cell-derived mediators such as TNFa and various chemokines, as well as on the expression of adhesion molecules on leukocytes (e.g. VLA-4, CD11/18) and vascular endothelial cells (e.g. VCAM-1, ICAM-1, E-selectin). Products of these leukocytes have several functions First, they cause the second phase of bron-choconstriction, mucus secretion, and airway swelling second, they cause tissue destruction third, they launch and entertain the chronic inflammation. 

Cadherins are a superfamily of Ca2+-sensitive cell-cell adhesion molecules, which cause homophilic cell interactions. Cadherins can be divided into different subfamilies, namely, classical cadherins, desmosomal cadherins, protocadherins, and nonconventional cadherins (7TM cadherins, T-cadherin, FAT). Classical cadherins are often denoted by a prefix reflecting their principal expression domains e.g., E is epithelial, N is neuronal, and P is placental. However, this classification is not stringent, as for instance E-cadherin can also be found in certain neuronal tissues, and N-cadherin is also found in epithelial cells. Among the desmosomal cadherins, two subfamilies can be distinguished the desmocollins 1-3 and the desmogleins 1-4. 

The extracellular domain of cadherins consists of a variable number of a repeated sequence of about 110 amino acids. This sequence is termed the cadherin repeat and resembles in overall structure, but not in sequence, the Ig like domains. The cadherin repeat is the characteristic motive common to all members of the cadherin superfamily. Classical and desmosomal cadherins contain five cadherin repeats, but as many as 34 repeats have been found in the FAT cadherin (see below). Cadherins are calcium-dependent cell adhesion molecules, which means that removal of Ca2+, e.g., by chelating agents such as EDTA, leads to loss of cadherin function. The Ca2+-binding pockets are made up of amino acids from two consecutive cadherin repeats, which form a characteristic tertiary structure to coordinate a single Ca2+ion [1]. 

Integrins, selectins, cadherins, claudins and other cell adhesion molecules are involved in the interaction of cells with other cells or with extracellular matrix components. Some of them also serve as receptors by inducing outside-in or additional inside-out signaling. 

Inhibition of inflammatory cytokines (Fig. 2) Humanized monoclonal anti-TNF antibodies (Infliximab (Remicade ), Adalimumab (Humira )) bind with high selectivity to human TNF-a and neutralize its activity. Thereby, infliximab decreases the effects of enhanced TNF levels during inflammatory disease such as production of proteases, chemokines, adhesion molecules, cyclooxygenase products (prostaglandins), and proinflammatory molecules such as interleukin-1 and -6. The antibodies may also recognize membrane-bound TNF-a on lymphocytes and other immune cells. These cells may subsequently become apoptotic or are eliminated via Fc-receptor-mediated phagocytosis. 

CD163 (Scavenger receptor) Adhesion molecules (ICAM-1, E-selectin)... 

Parallel to orchestrating acute inflammatory processes by providing an optimal milieu of cytokines, mediators, and adhesion molecules in order to recruit and activate effector cells to the site of infection, dendritic cells also setve as professional antigen-presenting cells for cells of the adaptive immune system ( antigen presentation ... 

In the specialized environment of secondary lymphoid tissues such as lymph nodes or spleen, dendritic cells provide the requirements for naive T-lymphocytes to become activated and to proliferate. The professional antigen-presenting cells present peptides in MHC II, express costimulatory molecules, and release cytokines into the immunological synapse, which is formed by the antigen-presenting cell and the naive T-lymphocyte. Thus, cells of innate immunity initiate and facilitate the activation of naive lymphocytes, and it is easily conceivable that their cytokines and adhesion molecules will instruct the naive T-lymphocyte during activation and differentiation to T-effector cells. 

The vascular endothelium plays an important role in regulation of vascular tone and permeability. Dilatation of arterioles to increase blood flow and constriction of endothelial cells of postcapillary venules causing exsudation of plasma constituents illustrates the complex nature of this cell type. Moreover, by expression of adhesion molecules and secretion of chemokines endothelial cells play an important role in the recruitment of leukocytes to the inflamed area. Endothelial cells express two basic types of adhesion molecules on their surface ... 

Inflammation. Figure 1 Sequence of events in the recruitment of leukocytes in postcapillary venules adjacent to injured tissue. At the site of lesion, diverse reactive substances stimulate the endothelium to produce inflammatory cytokines, chemoattractants and other inflammatory mediators. The cytokine-activated endothelium expresses adhesion molecules that lead to the low affinity interactions between leukocytes and endothelium, which is mediated by selectins and described as rolling. Subsequently integrins mediate the firm adhesion of leukocytes, which allows emigration of the cells from venules into the interstitial compartment. Activated mast cells, PMNs and macrophages secrete cytokines (TNFa), lipid mediators (LTB4) and other inflammatory players (histamine, NO). 

IFN- 3 reduces the induction by inflammatory cytokines of adhesion molecules and of MHC class I and II complex on endothelial cells, a process preceding attachment and transendothelial migration of T-cells. These anti-inflammatory effects of IFN- 3 exemplify antagonistic actions of type I and type IIIFN. There is, indeed, much clinical evidence for the involvement of IFN-y in inflammatory processes - through activation of iNOS and subsequent secretion of NO - leading to the establishment of autoimmune diseases as for instance in rheumatoid arthritis. 

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