Regulation of leukocyte adhesion and signaling in inflammation and disease

Regulation of leukocyte inflammation Immunology, Biology, Food surveillance adhesion molecules members nition National and Drug system Irutitute ofDental ofMinnesota, central which to Ig superfamily, between leukocytes, provide trafficking, host include of the These integrins provide a recog- endothelial recruitment and unresolved cells synthetic fibronectin integrin play, and recruitment tion in and J. vivo. for the Rio!. inhibit roleS develop normal, normally, but exhibit and cell-matrix movement, and essential system, and recruitment and to sites pendent binding members, mers interactions on specific selectins, and the containing [1-4]. Adhesive cell regulate division, interactions are gets, lethal genetic [7-9]. mice deficient (VCAM-1), Null specific are de- molecule deletions Consistent in and ligands, fibronectin of the integrin redundancies of the cx3, C 4, or with the necessity Ut5 these adhesion in vivo, with integrins for nontra- process the corresponding immune can 11are criti- pathways. interfere with leu- to sites of inflamarea has become an anti-inflammatory CELL [21]. leukocyte matrix and interactions for designing 32 in the adhesive adhesion re- or extracellular in vitro and recruitment and consequently this focus and a role i affinity coordinated of inflammatory binding fol- of higher or simultaneous cells is a combiinteractions agents. ADHESION AND Cell adhesion plays system by initially and part mediated by a central role the selectins, in the tethering integrins, function leukocytes of the to the and immune endothelium then enabling their emigration from the vasculature of tissue specific homing and recruitment at sites An effective host response as of to pathogens, in- 3 Abbreviations: f i chain in binding mi- endothelium, as the chemokines of these different interactions these inflammation. associated a and nature of these adhesion mutations despite vascular of order, on endothelial ICAMs GRR, cell 1). [5, 6], and the be a sequential regardless to evolution families (Table intra- [13-17] and appear phenotypically leukocyte adhesion and induction may adhesion lethal and ceptors molecules is underscored in mice genetically engineered to delete (knock out) members of the adhesion molecule are or selectins also gene products including carbohydrateimmunoglobulin (Ig) superfamily glycoprotein integrin family of heterodinoncovalently The essential in either the 1). INFLAMMATORY RECRU ITMENT the cell and maintenance of the immune responses, and wound healing. Adof leukocytes during tissue of infection or inflammation mutations dependent on leukocyte Recent evidence also suggests Blocking communica- and for (ICAM); are viable, impaired molecules such [20]. Engagement cal 1996. provide their environment processes of death. to development inflammatory hesion homing subunits cell of Cytokine Medicine, its counterreceptor, cytokine-mediated important cells and biological [12]; ditional process gands INTRODUCTION tion between fundamental DivLsion and homozygous L-selectins by kocyte mnation Cell-cell and molecule (Table adhesion inflamma- 789-796; adhesion However, in vitro, to limit 59: with leuko- transduction mice subunit cellular interactions [ 18, 19]. molecules Selected which signal hand, integrin lowed signal pivotal other 12 between continued activation on activation Leukoc. ofllealth ofPathology Leukocyte adhesion at an inflammatory site natorial process, involving initial low-affinity interinfec- and to the adhesion intervention. peptides, binding adhesion leukocyte Based targets Institwes Department gration and cell-matrix phenotype and contribute persistent interactions potential block can inflammation. adhesive provide cyte of these pathways and the the the and defense. selectins, Cell-cell leukocyte Dysregulation transduction National Maryland Minneapolis inflammation. also influence function. Research, Bethesda, and matrix molecules. Leukocyte-endothelial actions initiate recruitment at sites of injury, tion and interactions in and J. B. McCarthy AdminLstration, Cell adhesion molecules for cell communication, immune and G. M. Feldman, Cellular Abstract: foundation and signaling and disease S. M. WahI, Univers#{252}y adhesion tar- chain are also for 1 i integrins, vascular cell adhesion molecule also die in utero [10, 11]. On CS, gamma molecule; tyrosine kinase; adhesion molecule; cx, interferon-y; Bldg. 30, Journal of Leukocyte 1995; Cell MD revised Biology kinase; intercellular interleukin-1; MadCam, vascular Bethesda, 27, adhesion ICAM, activators S. M. WahI, 331, Received November January 2, 1996. and VCAM-1. Dr. Rm. focal JAK, mnucosal platelet-endothelial transducers factor-a; requests: IL-i, antibody; PE-CAM, signal FAK, Ig, immunoglobulin; monoelonal molecule; Reprint NIH, IFN-y, necrosis segment; region; mAli, STAT, tumor connecting response Janus addressin cell adhesion oftranscription; cell adhesion Immunology TNFmolecule-i Section, NIDR, 20892. December Volume 29, 59, 1995; accepted i9t ) , 789 TABLE 1. Consequences of Gene Null Phenotype Mutation (5presumptive 3 Day Targeting of Adhesion Molecules of Homozygotes primary 1 postnatal Reference target) [7} lethal 5kidney Embryonic 0(4 [8] lethal allantois-chorion fusion 5heart cx5 Embryonic I1 formation Embryonic 5inner [9] lethal *me5 eflfl [5, lethal cell 6] mass Similar to LAD [12] E-selectin Normal phenotype [15] L-selectin Normal phenotype [16]. (CD18) 2 ‘1’recruitment ,t,lymphocyte P-selectin Normal [17j homing [13, phenotype 14] .Lrecruitment Normal P-selectin/ICAM [13] phenotype Lrecruitment Normal, ICAM [13] phenotype ‘1. recruitment VCAM-1 Embryonic lethal [10] 5allantois-chonon fusion 5heart Fibronectin jury, or foreign antigen leukocytes, but matory disease pression constitutive of requires specific and inducible lectin) and members VCAM-1) [22]. The common structure main, sus domains the are Leukocyte sugars, [1, cally the 2]. Within of short rapid tethered and after supports transient mobilization leukocytes of the become mediators. of inflammatory ticularly P-selectin important in acute inflammatory may also contribute to chronic The events because of its prolonged expression Following the low-affinity interactions the site stimuli 790 and leukocytes of infection stimulates Journal of that Leukocyte Biology leukocyte and to the the leukocytes enat release of inflammatory and activation of inte- Volume 59, June 1996 adhesion receptor-ligand in response ICAMs, markedly for additional molecules interactions to chemotactic which contain up-regulated including promote of a different are expressed functionally responsive tion. In this way, and leukocytes appropriate tumor ages (Fig. the interaction is intensified necrosis factor- and bind Mac-i, and heterodimers, inactive to piSO,95 coin- with one (CDiib), of three or a, state become am leukocyte and arrest between only and are cytok- and activa- endothelial within the cells locality of signals. to the 32 (CD18) integrins, which mediate interactions predominantly through ICAM link1), members of the 130-kDa i (CD29) integrin family bind not also to extracellular heterodimers, in an endothelial recognize complexed (CDlia), during inflammatory In addition cell-cell CCL The Ig domains to inflammatory (IFN-y), chain adhe- of the agile leusubjacent space [24]. (IL-i), interferon-y VCAM). stronger migration into the signals interleukin-1 and endothe- (ICAMs, characteristic in response 2 (CD18) a subunits, posed are par- responses, but inflammatory [23]. between These ( CDiic), lo- selectins, selectins concentrate or injury, the the expression with a protein susceptible influence dothelium ter- injury, as counterreceptors the Ig superfamily members LFA-1, on circulating leukocytes [18]. These P-se- related tissue serve intracellular a (TNF-a), including from hal ines consen- molecules extending 2, a do- for E- and that grins sion and spreading to facilitate kocytes through the endothelium cytoplasmic ligands mucin-type moments endothelium through loosely as certain lectin and X (sLe9 Lewis carbohydrates activated adhesion a domain counterreceptors as well backbone and by carbohydrate sialyl 0-linked of to inflamcell ex- N-terminal to transmembrane represented multiple accumulation can lead Endothelial of an domain, tetrasaccharide minal formation adhesion molecules includes glycoproteins (E-selectin, P-se- consisting connected [1]. lectins focal lethal 5mesodern of the Ig superfamily (ICAM-1 and selectin family of receptors shares an EGF-like repeats this excessive accumulation and tissue pathology. [11] Embryonic only to appropriate matrix molecules composed of the i any of nine different i50-200-kDa broad spectrum of adhesive potential ligands on cells but [3, 4, 18, 19]. These subunit together a chains, with matrix with exhibit proteins. a For example, sal lamina, fibronectin, on cell present surfaces, sesses multiple domains the arginyl-glycyl-aspartic region clots ha- [25], by integrins including (RGD) sequence, which is sponse rapidly to IL-i induced and of inflammation, on TNF-a as [30, well as endothelial 3i] and and rolling neutrophils bodies neutrophil, the [35, 36], but this mucosal different cell the extracellular also and coagulation, on sites of the proteins more including integrin tence extend and interaction ligand binding in [39], a5 1, and often occur and/or T cells also express or conformationally or proteolytic the cell surface recognition complex and can and bind ;z:-d.n ur.d “ HIV present sn a,h Tat #{176}* i TM o. oto Mn flhiond o.pondki - mk n l\\ - vt onscth ‘ n von WM.br spectrum diverse (Fig. (Fig. a variety i) to posof the leuor ex- compe- Fibronectin- Fig. 1. Leukocyte and integnn 7Intsgrtns myeloid integrins families lineage and and have their been (a11 33). on platelets receptors ligands. Members identified ofthe on cells A partial f 3, , of lymphoid listing and of ligands these adhesion can modulate cell-cell and cell-extracellular matrix sion [4i-47]. In the context of leukocyte recruitment, for is represented. [40]. Moreover, ligand itself must in be to facilitate interfiinto adhesive adhesive in- in and and P-selectin responses in platelet-endothelial cell mediates by a heparin-inhibitable molecule, mechanism, consistent of cell surface proteoglycan of an inflammatory and/or sponse, this represents exciting area of investigation. focused on polypeptides nal (Hep-2) heparin-binding promotes lymphoid and ment suggests cyte emerging In this tumor cell Wah! of collaborative et a!. this involvement immune and regard, adhesion The proximity sites within cell surface proteoglycan the affinity state of integrins recognition with re- potentially interest has derived from the carboxyl-termidomain of fibronectin, which [50]. (CS-i) a potential interactions in cellular recognition is known regarding the . an leuthe PE-CAM cell exact mechanism in the development area en- 48] and to inhibit [46]. In addition, adhesion a role for cell surface proteoglycans relatively little of CD3 i Although modify they [46, vitro leukocyte-endothelial cc41 iand of macromolecules factors, with L-selectin kocyte rolling adhe- proteoglycans have been implicated of cytokines [43, 44]. Furtherhave been shown to interact pendent mechanisms and integrin-binding interac- may also play a role events. This molecularly dothelial cell surface in localized presentation more, glycosaminoglycans [49] of of growth I (CD31), levels group factor VCAM not all ligands augmented of leukocyte proteoglycans and binding d fi&on.ctki to include proteins and to their enhances ‘\ 50 integrin. Although soluble for a5f i, its deposition fragmentation structurally w.d t.n..c’n M.dCAM are up-regulated inflammatory me- competent action with the appropriate bronectin is a poor ligand tions, cellular o4 1 extracellular signaling. exposed teractions. Expanding J __ ..fIbron.ct$n can be triggered Activation of the prior addition matrix - ‘\N___ thnjmbo. \ vI onsdIn ROD ao ’), an integrin. While many expressed on mononuclear found in the circulation and a4 i after activation to integrin activation, the 0(4 1, __ _) ROD) #{163}zv 1 than appear and activation and/or expression to inflammatory mediators. must HEPI1, collagen proteins integrins binding, 1 i subunit-containing integrins on monocytes following challenge with diators fIbronscdn( S-1, [37]. (a4 ) beyond complement diversity, of ligand receptors fmdnogs - I 3hn 1 recog- a3 1, (a1131, a21 i, and osteopontin bind to the same site on integrins are constitutively kocytes whether they are travascularly, in response 96) ‘C3b with integrins cellular counterreceptors as bacterial and viral of this multiple (p150, 1 critical (MadCam) 3i many ligands fibrinolytic [38]. In support axt Echovirus fibronscVn ft4 not interacts molecule vitronectin, matrix molecules and such diverse molecules sess \ associ- is particularly selectively leukocyte matrix integrin X t nInki fibronectin a2f31, a3f i, 0(4133), laminin Moreover, -‘CAM. initial but subunit VCAM-i it adhesion domains thrombospondin, i). because to fibronectin, cell-binding aLt Z(LFA-1) cx.4 i inte- cell, a The heterodimer 0c4137 addressin In addition (ai1 t, -n n - -.-- comparable to selectthis specificity, anti- to recognize homing, fact ;z:-f dnogsn ‘CAM. a2 %% in lymphocyte nize [32]. chain cx (Mac-1) a1 1 re- inducibly 33]. The mediate mononuclear recruitment with UGANDS It 2h1t.gnns1 lnt.grlns at sites and AND ThEIR ‘ _s _PlY ot41 i inhibit to ates of lymphocytes, [34]. Reflecting in increased constitutively expressed on other cell types [2i, 32, grin interactions with VCAM-i may capture ins on cells INTEGRINS I 111 a3 1 (CS-i) containing the LDV sequence recognized by a4 i (VLA-4) [26]. The a4 i also serves as a receptor for sites within the first and fourth Ig-like domains of VCAM-1, a member of the immunoglobulin superfamily [27-29]. VCAM-1 I LEUKOCYTE pos- (VLA-3), and other infibronectin heparin-binding connecting segment domain with (VLA-5), (Fig. i). Within the is an alternately spliced tegrins matrices, in blood recognized acid as1 i interacts in plasma, and by RGD-indeof proteoglycan the 33-kDa frag- interaction RGD-independent Leukocyte between receptors [5i] [52]. Moreover, adhesion region and signaling that may leukoof fi- 791 bronectin implicates a role for such tory events, consistent with glycan binding peptides fibronectin mnation to inhibit [53, to [55, gelatinase and the cytokines [39] matrix. tracellular (MMP-l, matrix MMP-2) remodeling [60]. phenotype facilitates defense. site, leukocytes stimuli. These and activating and function their recruitment types molecules binding sites enables the matory functions. influenced chemotactic occurs cules and signals requirement events Besides transduction pathways regulatory receptors, of ad- the high-af- carry out inflammation, their tissue inflamadhesion responses [6i]. is reflected by diseases. ACTIVATION the also adhesion modify associated molecule-li- intracellular with integrins can Thi tive cells themselves, action because IFN-y cell signal activation. function IFN-y pathogens early response genes, dimerization from the cell transduced complex through adhesion of maturation-inducing tracellular tors, of 792 matrix initiating NF-KB Journal has protein transcription of Leukocyte been molecules stimuli. shown tyrosine factor, Biology Signals form part Adhesion to engage integrin phosphorylation, and induction members propagate of to transcription) a Volume 59, June to bind [70]. receptor to IFN- their (IFN-yRa activitates the phe+ several high-affinity Fc recep- which IFN- Janus tyrosine kinase [7i-74]. In turn, these phosphorythe signal through tyrosine phos- latent 9i-kDa cytoplasmic the STAT (signal transducers family [75, 76]. Phosphorylated homodimerize, migrate DNA-binding ‘y-stimulated transcriptional transcription to the nucleus, activator of Fc’yRI protein and activators STATs and serve responsible and other genes [7i, 73, 75, 77]. Evidence indicates stimulation of monocytes can be dramatically enced through cellular interactions with of then as a for IFNearly re- sponse IFN-’y that influ- extracellular ma- trix. When monocytes fibronectin cell monocytes were binding to intact CS-i does idly enhances not increase fibronectin independently the response of ing alone resulted agonists, TNF was minimally RGD and and or to the CS-i, in the expression of FcyRI Although adherence of or matrix-bound induce FcyRI to IFNy in transcription sion to fibronectin to fibronectin IFN-y-induced [78, 79]. recep- soluble adhered peptides, 79] (J. B. McCarthy et al., lar fashion, both neutrophil activation 1996 foreign brings about rapid transmission of membrane to the nucleus through of this to ex- certain its ability of two receptor-associated belonging the pro- to Fc region of IgG (FcyRI), clearance [7i]. Ligand-induced ‘1 receptor phorylation not further to govern including the conserved phagocytic nificant macrophages. IFN-y transcriptionally br for promotes (JAK) family lated kinases but responses repertoire to its bipartite monocytes activation extracelcytokine cells [69]. through monocytes to receptor immune presence of IFN-’y, the was markedly enhanced maturation of the helper for to be pro- which escape from this antiproliferathey lack the accessory factor-i (AF-i biochemical signals to the interior of the cell involving activation of cytoplasmic tyrosine kinases and modulation of gene expression [62-67]. During the process of adhesion and migration through endothelium and subendothelial basement membrane and into underlying tissues, undergo appear on monocyte/macrophages on to is a member responsible actions of Th2 via that of cytokines IFN-y lymphocyte-derived cell-mediated and that recognition is a Thi of the Thi AF-i) As to transduce castyrosine mediators whose proliferation chain) signals expressed, thereby contrast, these mole- inflammatory-based may of of antibodies to adhesion and other blocking agents in attachment, interactions and enter interactions mediating gand inhibits motes kinetics combination in pathologic CELL that or of soluble by cellular matrix. notypic and functional Binding of IFN-y persist effects influenced lular rein leukocytes transiently In family functions beyond cell participation adhesive INFLAMMATORY foundly with response. communication molecules for and cytokine interact cellular I receptors the signaling are augmented or costimulated this regard, evidence suggests can ex- may the profound inhibitory molecules, peptidomimetics, immune and signaling As a factors, to persist physiologic integrin cell-to-cell to a the per- of the integrin-responsive signals triggering cytokine induction [62]. certain kinases and genes are directly integrin other genes and their products, rather than of the locally. and the from integrin Although responsive, of and an kinase in monocytes [62]. In contrast to some other cells, macrophages appear to express little focal adhesion kinase (FAK) [63], and its activation appears to be dissociable subenex- As part to be environment, by the as [62-64]. appears an augmented influence leukocytes of leukocytes and signaling molecules are limiting leukocyte recruitment. The the genes Syk effect are exposed stimuli magnify factors that contextual and cells In 59] dramatically of the are that 58]. [57, into cade, being directly triggered, integnn signaling. In [57, matrix metalloproteinses to recruitment, repair, infiltration The to molecules degradation matrix molecules mediate that regulate inflammatory host binding mediators movement through contributes and Ligand proteolytic of a leukocyte’s tracellular cruitment hesion inflam- migration of monocytes production of T cell 72-kDa by adhesion Further leukocyte component wall. inflammatory Within the lesional barrage of inflammatory secretion of chemotactic finity interplay of adheby chemotactic triggered dothelial the this complex are motivated vascular monocyte release petuate of chronic transendothelial stimulates the and Enzyme development through leukocytes traverse promotes 56] and ai t inflammatory in inflamma- of synthetic proteoHep-2 region of 54]. Once adherent sion molecules, signals the domains the ability from the as reflected of the unpublished [80] and in enhanced RGD mRNA, FcyRI results). mast cell responses or it rapby a siggene [78, In a simi[8i] adheto the IgG, whereas fibronectin bindstimulatory. However, in contrast to fibronectin, binding substantially of monocytes down-regulated expression (Fig. 2) proinflammatory role [82], for complexes that signaling and defining a selective can modify nents), will to immune IFN-y thereby monocyte FcyRI integrin-ligand The ability of ligation to mimic and receptor IFN-y revealed cross-linking trix the ing (J. B. McCarthy the causal of receptors i synergism between with an et al., unpublished anti-ni converge to elicit inside the ceptors. cell, Both of signaling although kinases, that activation lation ofJAKi apparent two downstream remains signals of the integrins and IFN-’y molecules by tyrosine of STAT1a and within utilizing the sponse STAT1a, JAK2 must integrin the to better re- phosphorylation, fibronectin of electrophoretic DNA sequence region (GRR) a substantial was bronectin evident and and when stimulated of the increase with Defining IFN-y. and emerging that and other external stimuli the integrin and cytokine integration of complex inexpression products pathogens evidence matrix compoin governing the the augmented gene confront may in host OF ADHESION adhered the of leukocytes to the of Fc?RI set these cells up defense. TO CONTROL thology. unknown binds comfi- gies to control with persistent tions tissue not only block mecha- recruitment, disease and and dysfunction Based leukocyte migration and tissue basis of these to developing events. with molecules defense for the coordinated regumolecules. However, damage inflammatory matrix host the molecular is fundamental interference may and of normal of leukocyte adhesion, lead to inflammatory Understanding mechanisms evidence, proteins to cells evolution and serves as a paradigm and actions of adhesion dysregulation tivation may re- to adhesion nisms lation Moreassays gamma FcyRI promoter that in the DNA binding were stimuli macrophage is essential with peptides [78, 79]. mobility shift monocytes The is readily the Thus, extracellular factors to cytokines REGULATION INFLAMMATION phosphory- costimulated representing proteins and ofSTATia in monocytes the paths IFN-y recruitment Augmented other as unclear. cross and control (p9i). kinases minutes and adherent on the basis plex response the and well pathways. Such crosstalk between pathways facilitates flammatory for or this may involve some distinct protein tyrosine at some point, they appear to share JAK1 and JAK2 IFN-y over, a cooperative appears it signaling of cells (Fig. 2). signaling Whether integrins two responses integrin signal- paths of signaling to the nucleus are distinct and IFN-y or whether the pathways intersect However, as these to ma- results). signals, supports a role for insoluble nents and other environmental adhesion a likely requirement for in the potentiation of IFN-y these or direct signals (e.g., cytoskeletal compoprovide key insight into the cooperativity of signal- ing. antibody propagate largely strate- associated on emerging adhesive but also acpa- ablate interacactiva- C?D Ns GENE ISRE/GAS/GRR L:\J- 7cz:k. , Cell Membrane Fig. is mediatedthroughtheJak-Statsignalingpathway. 2. ModulationoflFN-ysignaltransduction.IFN-ysignaltransduction is inhibited (-) by adhesion to immune complexes but substantially augmented (+) when the cells Wahi adhere et a!. MonoeytelFN-ysignaling to fibronectin. Leukocyte adhesion and signaling 793 lion pathways associated Moreover, since evidence adhesion to matrix prevents disruption of these lution of inflammation In pursuit ies (mAbs) has also models, of to selectins [85, targeting to ICAM-i infiltration. the of T cells suppressed implicate was not may as well late leukocyte mAb may and cell monolayers inhibited into the extracellular can whether Al- disease the domain (Hep-2) RGD-containing tracellular matrix dampening macrophage also blocks recruitment with response consequence development lar matrices 79] RGD the surface adhesion in vivo as clearly Administration (SCW) response swollen and destruction [54]. mRNA Synovial in rheumatoid of the Journal “sticky” of arthritis circulating Leukocyte Biology [22, [90, as tissue, a with extracellu- on of ICAM-i, June local as cap- continued 1996 JAK2, signaling. and The treated ability cascade By the observed models, we can demonstrate not peptides mitigate adhesion, migration, and/or critical are to cyte and bridging the in vitro inflammatory that the synthetic recruitment signals but which perpetuation fibronectin efficacy of may be inflammatory peptides have been shown in other models of pathologic autoimmune vasculitis integrins VCAM the events explanation for pathways seen in and activation no with- to block in in vivo only was disrupted. and mice, effects pres- blockade of RGD with maturation in the STATia animals. of matrixexposed in phospho- a receptor the synovium this were increase with of inflam- identifica- to fibronectin a more satisfying of inflammatory with disease. In TGF- i spontaneous [53, 93] and (McCartney-Francis synthetic fibronectin also have all providing thetic bone. expression interrupt beyond adhesion provides the marked suppression [53]. favors 59, receptor adhesion consistent recent proc- ability and monocytes adhesion-induced JAK1, animals It is this Volume operative, arthritis and 92], cells. of the longer (FN/CH-I expression cell E-selectin rylation peptides subchondral endothelial including and deformed receptor before the in and of IFN-y-induced fibronectin peptides to When they expression elevated et knockof leuko- endothelial cell al., unpublished ICAM re- sults) appears to orchestrate a massive leukocyte infiltrate into several targeted tissues including heart, lung, and salivary gland. Inhibition of these autoimmune-like lesions by increased numbers of demonstrate aug- and ability the ofthe and for nature arthritis. on the the amplification. inflammatory in the synovial cartilage of integrin the liver the rheumatoid become cell Given after resides activation signal inflammation in an focused assessed RGD of question based of IFN-y, onset molecules have their the this leukocyte production. or compelling when of the were out leukocyte within where studies Soluble synthetic to have therapeutic to geneti- a persistent synovium, human shown new disease most peptides the potentiation 79], soluble processes but after the efficacious concerned of the answering complexity to influence particularly pep- in vitro in and of were of the studies until of SCW, of leukocytes of the one effects mediator that thereby of bacterial A streptococci ofprogressive molecules cell heparin- or CS-i involved, onset these difficulty peptides results be (J. B. McCarthy of the receptor-li- augmentation With the progression of inflammation, circulating mononuclear leukocytes levels RGD the signaling, [78, precipitates mimics joints of articular mented can the also IFN-y of the inflammation the from and synthetic group the closely Afflicted derived inflammatory within constituents signal model. animals and and adhesion the tion of integrin-dependent monocyte activation [78, out in to endothelial Interruption soluble from the role receptor the ence fibronectin adhesion activation with susceptible explored perpetu- degradation peptides Thus, administered to soluble of the signaling of integrin- from integrin enhance interferes fragments actions these we have matrix results). animal to stimu- multiplicity segment, inflammation experimental the at from multiplicity matory of fibronectin [53, 54]. Moreover, peptides inhibit the ability of ex- to unpublished the not esses the adhesion. derived CS-i the The established. arising entry consequently [54]. anti-inflammatory While inte- 2 that doses anticipated and administered were a T which leukocytes arthritogenic the matrix was of the swelling shown of the peptides binding soluble interaction 58], leukocyte by synthetic not only [57, interruption extracellular domain, tides in vitro with vitro, and gand been interfering In by of new receiving synovium questions with observations Because have sequences binding 794 therapy, antibod- [32]. ear other a4 i in inflammation, to and signaling. ture impaired emigra- recruitment to define peptide binding reported peptides including though and to impeding studies and even These the in addition responses studies inflammation. functions of selected cell to rats the subunits models activation systemically hypersensitivity, beyond suppress as a4 i In ongoing some [89]. incorporate pathways, 9i]. integrin disease inhibited mechanisms spleen monoclonal and of contact by 80% antibodies cally that 86] in model tion wall [83], endothelial counterreceptors [87] or antisense oligonucleotides Interestingly, was et al., shown in inflammatory cell-dependent based apoptosis and ates the inflammation and associated tissue injury. When fibronectin-specific peptides were administered proved to be effective [88]. In the majority of these administration of mAbs was initiated at the onset response and virtually abolished mononuclear cell the grins cell to anti-inflammatory have pathology ternatively, antibodies endothelial approach of studies inhibit recruitment inflammatory phenotype. that integnn-mediated binding events may also facilitate resothrough such a mechanism [84]. of this a number with the suggests offer reveal contact inflammatory interventions. Cell adhesion molecules communication, trafficking, and the that 2 Hep-2 life the of the peptides hypersensitivity evidence an important CSi, prolongs studies in murine compelling RGD, FN/CH-V) Additional efficacy peptides peptides, and that avenue provide the and immune [94], cell-binding syn- for pursuing anti- foundation surveillance for cell cen- tral to host defense, and with further understanding of normal adhesive events it may become possible to exploit these relationships in our attempts to diagnose and control inflammatory processes that have gone awry. Not only might we be able to leukocyte-mediated therapies, persistent inflammation pathophysiology but it may in conditions host inhibit also in which response be through possible antiadhesion to promote inflammation, to infections wound may 26. and or the 27. be deficient. 28. REFERENCES 29. 1. 2. 3. 4. 5. Leaky, L.A.. (1992) Selectins: interpreters of cell-specific information during inflammation. Science 258, 964-969. 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