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And Extravasation in Vivo Adhesion, Peptides Induce Leukocyte Rolling Proteinase-Activated Receptor-2-Activating Peptides Induce Leukocyte Rolling, Adhesion, and Extravasation In Vivo This information is current as Nathalie Vergnolle of September 25, 2021. J Immunol 1999; 163:5064-5069; ; http://www.jimmunol.org/content/163/9/5064 Downloaded from References This article cites 51 articles, 17 of which you can access for free at: http://www.jimmunol.org/content/163/9/5064.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 25, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 1999 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Proteinase-Activated Receptor-2-Activating Peptides Induce Leukocyte Rolling, Adhesion, and Extravasation In Vivo1 Nathalie Vergnolle2 Proteinase-activated receptor 2 (PAR2) has been suggested to play a role in inflammatory reactions. Because leukocyte-endothelial cell interactions are critical events during inflammatory reactions, and because PAR2 is expressed both on endothelium and leukocytes, we have examined the effects of PAR2-activating peptides (PAR2-APs) on leukocyte rolling and adhesion in mesenteric venules and on leukocyte recruitment into the peritoneal cavity. Using intravital microscopy, leukocyte rolling, flux, and adhesion m in rat mesenteric postcapillary venules were quantified. Topical addition of PAR2-APs (10 M) for 1 min to the superfused venule induced a significant increase in leukocyte rolling and adherence. The increase in leukocyte adherence was not affected by pretreatment with a mast cell stabilizer (sodium cromoglycate) nor by prior degranulation of mast cells with compound 48/80. Nonetheless, both leukocyte rolling and adhesion were completely inhibited by pretreatment with a platelet-activating factor Downloaded from receptor antagonist (WEB 2086). Intraperitoneal injections of a selective PAR2-AP (SLIGRL-NH2) caused a significant increase in leukocyte migration into the peritoneal cavity. The effect of SLIGRL-NH2 on peritoneal leukocyte infiltration was completely inhibited by WEB 2086. These data suggest that PAR2 activation could contribute to several early events in the inflammatory reaction, including leukocyte rolling, adherence, and recruitment, by a mechanism dependent on platelet-activating factor release. The Journal of Immunology, 1999, 163: 5064–5069. http://www.jimmunol.org/ 3 roteinase- activated receptors (PARs) are G protein-cou- In contrast with PAR1, very little is known about the physio- pled receptors that are activated by the cleavage of their logical and pathophysiological role of PAR2. Previous studies have shown that PAR activation caused relaxation of rat aorta rings and P N-terminal domain by proteinases (1–6). The proteolytic 2 cleavage of the N-terminal region of PARs unmasks a new N- that this effect was dependent on the integrity of the endothelium terminal sequence that acts as a tethered ligand that binds and and was mediated by the production of nitric oxide (10, 14). In rats activates the receptor itself. Four members of the PAR family have or in mice in which the gene for PAR1 has been deleted, the i.v. injection of a PAR -activating peptide has been shown to produce been cloned yet. PAR1, PAR3, and PAR4 are activated by throm- 2 a marked fall in blood pressure (15–17). The up-regulation of bin, and PAR2 is activated by trypsin or by human mast cell by guest on September 25, 2021 tryptase (7–9). Short synthetic peptides based on the peptidic se- PAR2 mRNA in cultured endothelial cells after the addition of a a quence of the tethered ligand revealed by proteolysis (PAR-acti- IL-1 , TNF- , or LPS constitutes one of the first arguments in favor of a possible role for PAR during inflammation (18). More- vating peptides, PAR-APs) can selectively activate PAR (e.g., the 2 1 over, we showed in a recent study that the injection of selective peptide TFLLR-NH ), PAR (e.g. SLIGRL-NH , SL-NH ), and 2 2 2 2 PAR -APs (SL-NH and Tc-NH ) into the rat paw can cause an PAR (e.g., GYPGQV-NH ). PAR is activated by thrombin, but 2 2 2 4 2 3 acute inflammatory response characterized by edema and granu- cannot be activated by synthetic peptides based either on its own locyte infiltration (19). revealed tethered ligand or on the other PAR-APs (4). SL-NH , the 2 Polymorphonuclear leukocytes are key cellular mediators in peptide corresponding to the rat PAR2 proteolytically revealed se- host defense against injury and infection. The ability of these cells quence, has been shown to be highly specific for PAR2 activation to recognize the vascular endothelium proximal to sites of infec- (10, 11). Another PAR2-AP has been designed: trans-cinnamoyl- tion, to adhere to the vessel wall, and to transmigrate into the site LIGRLO-NH2 (Tc-NH2), and appears to be a highly selective ag- of the wound represents one of the early steps of the inflammatory onist for PAR2 activation (12, 13). reaction. Leukocyte rolling, adhesion, extravasation, and migration to the inflammatory site allow phagocytes to get to their target, thereby providing a defense against invading pathogens. From the studies summarized above, it appears that PAR2 activation can be Department of Pharmacology and Therapeutics, Faculty of Medicine, University of hypothesized to play a role in inflammatory reactions by causing Calgary, Calgary, Alberta, Canada vascular changes and granulocyte infiltration. It has been shown Received for publication June 14, 1999. Accepted for publication August 19, 1999. that PAR2 is highly expressed both on the endothelium and on The costs of publication of this article were defrayed in part by the payment of page leukocytes, in particular neutrophils (20). However the effect of charges. This article must therefore be hereby marked advertisement in accordance PAR activation on leukocyte-endothelial cell interactions has not with 18 U.S.C. Section 1734 solely to indicate this fact. 2 been reported to date. Therefore, we wished to determine whether 1 N.V. is supported by a fellowship from the Canadian Association of Gastroenter- ology, Abbott Laboratories, and the Medical Research Council of Canada. PAR2 activation might induce changes in leukocyte rolling, adhe- 2 Address correspondence and reprint requests to Dr. Nathalie Vergnolle, Department sion, and extravasation. Using intravital video microscopy, the ef- of Pharmacology and Therapeutics, University of Calgary, 3330 Hospital Drive NW, fects of two PAR2 agonists, SL-NH2 and Tc-NH2, were tested on Calgary, Alberta, T2N4N1 Canada. E-mail address: [email protected] mesenteric venule diameter and leukocyte rolling and adhesion. In 3 Abbreviations used in this paper: PAR, proteinase-activated receptor; PAF, platelet- addition, the ability of PAR2 activation to recruit polymorphonu- activating factor; PAR-AP, PAR-activating peptide; Tc-NH2, trans-cinnamoyl- clear leukocytes was tested by injecting a selective PAR2-AP i.p. LIGRLO-NH2; LR-NH2, LRGILS-NH2; LSIGRL-NH2, LS-NH2; SLIGRL-NH2, SL-NH2. and monitoring the extravasation of leukocytes into the peritoneal Copyright © 1999 by The American Association of Immunologists 0022-1767/99/$02.00 The Journal of Immunology 5065 cavity. Finally, the role of mast cells and the role of platelet- activating factor (PAF) in the PAR2-AP-induced increase in leu- kocyte adherence, rolling, and extravasation were investigated. Materials and Methods Animals Male Wistar rats (175–200 g) were obtained from Charles River Breeding Farms (Montreal, QC, Canada). Animals had free access to food and water and were housed under constant temperature (22°C) and photoperiod (12-h light-dark cycle). All experimental procedures were approved by the An- imal Care Committee of the University of Calgary and were performed in accordance with the guidelines established by the Canadian Council on Animal Care. Leukocyte rolling adherence in vivo Rats (n 5 5 or 6 per group) were fasted a minimum of 15 h before the beginning of the experiment. The animals were anesthetized with sodium FIGURE 1. Time-dependent changes in flux of rolling leukocytes in pentobarbital (60 mg/kg i.p.) and a midline abdominal incision was made. naive rats after superfusion with control peptide (LR-NH2)orPAR2-AP Downloaded from Rats were then placed in a supine position on an adjustable Plexiglas mi- (SL-NH2), and in vehicle-treated or WEB 2086-treated rats after the ad- croscope stage. A segment of the midjejunum was exteriorized through the 6 5 dition of SL-NH2. Values are means SEM of n 6 for groups of naive abdominal incision, and the mesentery was prepared for in vivo micro- rats and n 5 5 for vehicle- and WEB 2086-treated rats. p, Significantly scopic observation, as previously described (21). Briefly, the mesentery different from the control peptide, p , 0.05. #, Significantly different from was draped over an optically clear viewing pedestral that allows for tran- , sillumination of a 2-cm2 segment of mesenteric tissue. The temperature of the vehicle-treated group, p 0.05. the pedestral was maintained at 37°C with a constant temperature circula- tor. The exposed bowel was covered with saline-soaked gauze to minimize tissue dehydration, and the mesentery was superfused with warm (37°C) Leukocyte extravasation http://www.jimmunol.org/ bicarbonate-buffered saline, pH 7.4. The mesenteric microcirculation was observed using a microscope (Nikon optiphot-2) with a 325 objective lens Three groups of rats received a 1-ml i.p.
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