Lodish H. - Molecular Cell Biology (5ed, Freeman, 2003) (794361), страница 97
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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. ❚229Gap Junctions Composed of Connexins AllowSmall Molecules to Pass Between Adjacent CellsEarly electron micrographs of virtually all animal cells thatwere in contact revealed sites of cell–cell contact with a characteristic intercellular gap (Figure 6-31a). This featureprompted early morphologists to call these regions gap junctions.
In retrospect, the most important feature of these junctions is not the gap itself but a well-defined set of cylindricalparticles that cross the gap and compose pores connectingthe cytoplasms of adjacent cells—hence their alternate nameof intercytoplasmic junctions. In epithelia, gap junctions aredistributed along the lateral surfaces of adjacent cells (seeFigures 6-1 and 6-5).In many tissues (e.g., the liver), large numbers of individual cylindrical particles cluster together in patches. This property has enabled researchers to separate gap junctions fromother components of the plasma membrane.
When theplasma membrane is purified and then sheared into smallfragments, some pieces mainly containing patches of gapjunctions are generated. Owing to their relatively high protein content, these fragments have a higher density than thatof the bulk of the plasma membrane and can be purified onan equilibrium density gradient (see Figure 5-37). When these(a)(b)Gapjunction50 nm50 nm▲ EXPERIMENTAL FIGURE 6-31 Gap junctions have acharacteristic appearance in electron micrographs. (a) In thisthin section through a gap junction connecting two mouse livercells, the two plasma membranes are closely associated for adistance of several hundred nanometers, separated by a “gap”of 2–3 nm. (b) Numerous roughly hexagonal particles are visiblein this perpendicular view of the cytosolic face of a region ofplasma membrane enriched in gap junctions.
Each particle alignswith a similar particle on an adjacent cell, forming a channelconnecting the two cells. [Part (a) courtesy of D. Goodenough. Part (b)courtesy of N. Gilula.]230CHAPTER 6 • Integrating Cells into Tissuespreparations are viewed in cross section, the gap junctionsappear as arrays of hexagonal particles that enclose waterfilled channels (Figure 6-31b). Such pure preparations of gapjunctions have permitted the detailed biophysical and functional analysis of these structures.The effective pore size of gap junctions can be measuredby injecting a cell with a fluorescent dye covalently linkedto molecules of various sizes and observing with a fluorescence microscope whether the dye passes into neighboringcells.
Gap junctions between mammalian cells permit thepassage of molecules as large as 1.2 nm in diameter. In insects, these junctions are permeable to molecules as large as2 nm in diameter. Generally speaking, molecules smaller than1200 Da pass freely, and those larger than 2000 Da do notpass; the passage of intermediate-sized molecules is variableand limited.
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