H. Lodish - Molecular Cell Biology (5ed, Freeman, 2003) (796244), страница 95
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In contrast, theextracellular region of L1-CAM has six Ig repeats and four fibronectin type III repeats. As with cadherins, cis (intracellular)interactions and trans (intercellular) interactions probably playkey roles in IgCAM-mediated adhesion (see Figure 6-3).The covalent attachment of multiple chains of sialic acid,a negatively charged sugar derivative, to NCAMs alters theiradhesive properties. In embryonic tissues such as brain, polysialic acid constitutes as much as 25 percent of the mass ofNCAMs. Possibly because of repulsion between the manynegatively charged sugars in these NCAMs, cell–cell contactsare fairly transient, being made and then broken, a propertynecessary for the development of the nervous system.
In contrast, NCAMs from adult tissues contain only one-third asmuch sialic acid, permitting more stable adhesions.Movement of Leukocytes into Tissues Dependson a Precise Sequence of Combinatorially DiverseSets of Adhesive InteractionsIn adult organisms, several types of white blood cells (leukocytes) participate in the defense against infection caused byforeign invaders (e.g., bacteria and viruses) and tissue damage due to trauma or inflammation. To fight infection andclear away damaged tissue, these cells must move rapidlyfrom the blood, where they circulate as unattached, relativelyquiescent cells, into the underlying tissue at sites of infection,inflammation, or damage. We know a great deal about themovement into tissue, termed extravasation, of four typesof leukocytes: neutrophils, which release several antibacterial proteins; monocytes, the precursors of macrophages,which can engulf and destroy foreign particles; and T and Blymphocytes, the antigen-recognizing cells of the immunesystem.Extravasation requires the successive formation andbreakage of cell–cell contacts between leukocytes in theblood and endothelial cells lining the vessels.
Some of thesecontacts are mediated by selectins, a family of CAMs thatmediate leukocyte–vascular cell interactions. A key playerin these interactions is P-selectin, which is localized to theblood-facing surface of endothelial cells. All selectins contain228CHAPTER 6 • Integrating Cells into Tissuesa Ca2-dependent lectin domain, which is located at thedistal end of the extracellular region of the molecule andrecognizes oligosaccharides in glycoproteins or glycolipids (see Figure 6-2). For example, the primary ligandfor P- and E-selectins is an oligosaccharide called thesialyl Lewis-x antigen, a part of longer oligosaccharidespresent in abundance on leukocyte glycoproteins andglycolipids.Figure 6-30 illustrates the basic sequence of cell–cell interactions leading to the extravasation of leukocytes. Variousinflammatory signals released in areas of infection or inflammation first cause activation of the endothelium.P-selectin exposed on the surface of activated endothelialcells mediates the weak adhesion of passing leukocytes.
Because of the force of the blood flow and the rapid “on” and“off” rates of P-selectin binding to its ligands, these“trapped” leukocytes are slowed but not stopped and literally roll along the surface of the endothelium. Among the23Endothelial activation andleukocyte attachment and rollingLeukocyte activation(PAF activates integrin)1Leukocyte(resting state)Selectin ligand(specificcarbohydrate)Focus Animation: Cell–Cell Adhesion in Leukocyte ExtravasationαLβ2integrinP-selectinPAFreceptorMEDIA CONNECTIONSsignals that promote activation of the endothelium arechemokines, a group of small secreted proteins (8–12 kDa)produced by a wide variety of cells, including endothelialcells and leukocytes.For tight adhesion to occur between activated endothelialcells and leukocytes, 2-containing integrins on the surfacesof leukocytes also must be activated by chemokines or otherlocal activation signals such as platelet-activating factor(PAF).
Platelet-activating factor is unusual in that it is aphospholipid, rather than a protein; it is exposed on the surface of activated endothelial cells at the same time thatP-selectin is exposed. The binding of PAF or other activatorsto their receptors on leukocytes leads to activation of theleukocyte integrins to their high-affinity form (see Figure6-28).
(Most of the receptors for chemokines and PAF aremembers of the G protein–coupled receptor superfamily discussed in Chapter 13.) Activated integrins on leukocytes thenbind to each of two distinct IgCAMs on the surface of en-ICAM-2EndothelialcellICAM-1Vesicle containingP-selectinExtravasation5PAFFirm adhesion viaintegrin/ICAM binding4▲ FIGURE 6-30 Sequence of cell–cell interactionsleading to tight binding of leukocytes to activatedendothelial cells and subsequent extravasation. Step 1 :In the absence of inflammation or infection, leukocytes andendothelial cells lining blood vessels are in a resting state.Step 2 : Inflammatory signals released only in areas ofinflammation or infection or both activate resting endothelialcells to move vesicle-sequestered selectins to the cellsurface.
The exposed selectins mediate loose binding ofleukocytes by interacting with carbohydrate ligands onleukocytes. Activation of the endothelium also causessynthesis of platelet-activating factor (PAF) and ICAM-1, bothexpressed on the cell surface. PAF and other usuallysecreted activators, including chemokines, then inducechanges in the shapes of the leukocytes and activation ofleukocyte integrins such as L2, which is expressed byT lymphocytes ( 3 ). The subsequent tight binding betweenactivated integrins on leukocytes and CAMs on theendothelium (e.g., ICAM-2 and ICAM-1) results in firmadhesion ( 4 ) and subsequent movement (extravasation) intothe underlying tissue ( 5 ).See text for further discussion.[Adapted from R.
O. Hynes and A. Lander, 1992, Cell 68:303.]6.5 • Adhesive Interactions and Nonepithelial Cellsdothelial cells: ICAM-2, which is expressed constitutively,and ICAM-1. ICAM-1, whose synthesis along with that ofE-selectin and P-selectin is induced by activation, does notusually contribute substantially to leukocyte endothelial celladhesion immediately after activation, but rather participatesat later times in cases of chronic inflammation.
The resultingtight adhesion mediated by the Ca2-independent integrin–ICAM interactions leads to the cessation of rolling and to thespreading of leukocytes on the surface of the endothelium;soon the adhered cells move between adjacent endothelialcells and into the underlying tissue.The selective adhesion of leukocytes to the endotheliumnear sites of infection or inflammation thus depends on thesequential appearance and activation of several differentCAMs on the surfaces of the interacting cells.
Different typesof leukocytes express specific integrins containing the 2subunit: for example, L2 by T lymphocytes and M2 bymonocytes, the circulating precursors of tissue macrophages.Nonetheless, all leukocytes move into tissues by the samegeneral mechanism depicted in Figure 6-30.Many of the CAMs used to direct leukocyte adhesion areshared among different types of leukocytes and target tissues.Yet often only a particular type of leukocyte is directed to aparticular tissue. A three-step model has been proposed toaccount for the cell-type specificity of such leukocyte–endothelial cell interactions. First, endothelium activationpromotes initial relatively weak, transient, and reversiblebinding (e.g., the interaction of selectins and their carbohydrate ligands). Without additional local activation signals,the leukocyte will quickly move on.
Second, cells in the immediate vicinity of the site of infection or inflammation release or express on their surfaces chemical signals (e.g.,chemokines, PAF) that activate only special subsets of thetransiently attached leukocytes. Third, additional activationdependent CAMs (e.g., integrins) engage their binding partners, leading to strong sustained adhesion.
Only if the propercombination of CAMs, binding partners, and activation signals are engaged in the right order at a specific site will agiven leukocyte adhere strongly. This additional example ofcombinatorial diversity and cross talk allows parsimoniousexploitation of a small set of CAMs for diverse functionsthroughout the body.Leukocyte-adhesion deficiency is caused by a genetic defect in the synthesis of the integrin 2 subunit. Persons with this disorder are susceptible torepeated bacterial infections because their leukocytes cannot extravasate properly and thus fight the infection withinthe tissue.Some pathogenic viruses have evolved mechanisms to exploit for their own purposes cell-surface proteins that participate in the normal response to inflammation. Forexample, many of the RNA viruses that cause the commoncold (rhinoviruses) bind to and enter cells through ICAM-1,and chemokine receptors can be important entry sites forhuman immunodeficiency virus (HIV), the cause of AIDS.
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