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Published online before print November 11, 2004
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6 integrin inhibits IL-1ß- but not TNF--induced neutrophil transmigration in vivo
Cardiovascular Medicine Unit, Eric Bywaters Centre for Vascular Inflammation, Faculty of Medicine, Imperial College London, Hammersmith Hospital, United Kingdom
1 Correspondence: Cardiovascular Medicine Unit, The Eric Bywaters Centre for Vascular Inflammation, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK. E-mail: s.nourshargh{at}imperial.ac.uk
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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6ß1 in neutrophil migration through the perivascular basement membrane, a response that in vivo appears to be associated with platelet/endothelial cell adhesion molecule-1 (PECAM-1)-mediated up-regulation of 6ß1 on the cell surface of transmigrating leukocytes. As the involvement of PECAM-1 in leukocyte migration is cytokine-specific, the aim of the present study was to investigate whether 6ß1 exhibited a similar profile of stimulus specificity in this context. The cytokines interleukin-1ß (IL-1ß) and tumor necrosis factor (TNF-) were used to elicit neutrophil migration in two murine models of inflammation, migration through cremasteric venules, as observed by intravital microscopy, and migration into the peritoneal cavity. The role of 6ß1 was investigated using an 6 integrin-blocking monoclonal antibody GoH3. In both models, GoH3 significantly inhibited neutrophil transmigration induced by IL-1ß but not TNF-. This cytokine-specific role of 6 integrin was associated with enhanced cell-surface expression of 6ß1 on transmigrated neutrophils (as compared with blood cells) in response to IL-1ß but not TNF-. Using lipopolysaccharide as an inflammatory stimulus in the cremaster muscle model, the study also provides evidence for the involvement of 6 integrin in leukocyte transmigration as mediated by endogenously generated IL-1ß. Collectively, the findings demonstrate that 6ß1 blockade inhibits neutrophil migration induced by exogenous and endogenous IL-1ß but not TNF-, observations that are associated with increased expression of the integrin on transmigrated leukocytes.
Key Words: inflammation • cytokine • leukocyte • adhesion molecules
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Despite its slow progress, significant advances have been made in the field of leukocyte transendothelial cell migration with molecules such as platelet/endothelial cell adhesion molecule-1 (PECAM-1), intercellular adhesion molecule-1 (ICAM-1), ICAM-2, junctional adhesion molecules, and CD99 being directly implicated in this response [4
]. Less is, however, known about the mechanisms that mediate leukocyte migration through the PBM, although a number of molecules have been strongly implicated [3
]. These include leukocyte proteases, such as neutrophil elastase, for which the field remains contentious [5
, 6
], and certain adhesion molecules, such as PECAM-1 [7
8
9
10
] and ß1 integrins, in particular, 6ß1.
The integrin 6ß1 is expressed on platelets [11
] and numerous cell types, including monocytes/macrophages [12
], neutrophils [13
], and endothelial cells [14
]. This molecule is the principal leukocyte receptor for laminin, the major structural, noncollagenous component of basement membranes, and anti-6ß1 antibodies have been shown to block the direct interaction of leukocytes with laminin [13
, 15
16
17
] as well as inhibit neutrophil transmigration through endothelial cells cultured on laminin [18
]. In agreement with these in vitro observations, we have recently found that an anti-6 integrin monoclonal antibody (mAb; GoH3) can inhibit neutrophil migration through interleukin-1ß (IL-1ß)-stimulated mouse cremasteric venules at the level of the basement membrane, a response that appears to be PECAM-1-dependent [19
]. However, as our findings to date have shown that the ability of PECAM-1 to mediate neutrophil migration through the basement membrane is cytokine-specific [i.e., PECAM-1 mediates neutrophil transmigration induced by IL-1ß but not tumor necrosis factor (TNF-); ref. 10
], the specific aim of the present study was to investigate whether 6 integrin blockade exhibited a similar cytokine-specific effect. Collectively, the results of the present study demonstrate that in agreement with our findings with PECAM-1, inhibition of 6 integrins suppresses neutrophil migration induced by IL-1ß but not TNF-, further supporting the concept that the roles of PECAM-1 and 6 integrins in mediating neutrophil migration through the PBM are functionally associated.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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were purchased from Serotec (Oxford, UK). Lipopolysaccharide (LPS) and Tyrode’s balanced salt solution were purchased from Sigma-Aldrich (Poole, Dorset, UK). The following rat anti-mouse primary antibodies were used: GoH3 [immunoglobulin G (IgG)2a, anti-6], 9EG7 (IgG2a, anti-ß1), MEL-14 (IgG2a, anti-L-selectin), and the neutrophil-specific antibody GR-1. These and their isotype-matched control mAb were obtained from BD Biosciences (Oxford, UK). Fluorescein isothiocyanate (FITC)-conjugated goat anti-rat IgG was purchased from Serotec. Alexa Fluor-conjugated secondary antibodies were purchased from Molecular Probes (Poortgebouw, The Netherlands). IL-1 receptor antagonist (IL-1ra) was a gift from Synergen (Denver, CO). TNF receptor-IgG (p55) and control chimeric antibody (cSF25) were gifts from Centocor Inc. (Malvern, PA).
Animals
C57BL/6 mice (20–25 g; Harlan-Olac, Bicester, Oxfordshire, UK) were used for all experiments.
Flow cytometry
Following an intraperitoneal (i.p.) injection of IL-1ß (10 ng) or TNF- (100 ng), blood (taken via cardiac puncture and diluted with the anticoagulant acid-citrate-dextrose in a 1:4 ratio) or peritoneal fluid from the same mice was incubated on ice with primary mAb. The binding of test mAb was detected after incubation with a F(ab')2 FITC-conjugated goat anti-rat IgG before analysis on an EPICS XL flow cytometer (Beckman Coulter, Fullerton, CA). Neutrophils were gated based on binding to the neutrophil-specific marker GR-1 and on forward- and side-scatter profiles. The relative fluorescent intensities (RFI) were calculated by comparing the binding of primary to isotype-matched control mAb.
Intravital microscopy
Wild-type C57BL/6 male mice (20–25 g) received an intrascrotal (i.s.) administration of rmIL-1ß (30 ng), TNF- (300 ng), or LPS (30 µg). Control groups of mice were injected with i.s. saline (400 µl). Some groups of mice were treated intravenously (i.v.) with the vehicle saline, anti-6 integrin mAb GoH3, or an isotype-matched control mAb (all at 3 mg/kg) 15 min before i.s. injection of the stimulus. In some experiments, the i.s. stimuli were coinjected with the TNF-ra (p55)-IgG fusion protein (10 µg/site) or a control chimeric protein cSF25 (10 µg/site) and/or IL-1ra (30 µg/site). Four hours after i.s. stimuli, the mice were anaesthetized by i.p. administration of ketamine (Ketalar, 100 mg/kg) and xylazine (Rompun, 10 mg/kg), and the cremaster muscle was surgically exteriorized for investigations by intravital microscopy, as described previously [10
]. The cremaster muscle was constantly superfused with Tyrode’s salt solution, and leukocyte-endothelial cell interactions were observed on a Zeiss Axioskop (Carl Zeiss Ltd., Welwyn Garden City, Herts, UK) fixed-stage, upright microscope fitted with water-immersion objectives (x20 and x40). Leukocyte responses of rolling, firm adhesion, and extravasation in postcapillary venules of 20–40 µm diameter were analyzed, as described previously [20
]. Rolling cells were defined as those cells moving slower than the flowing erythrocytes, and rolling flux was quantified as the number of rolling cells per minute moving past a fixed point for 5 min. Firmly adherent leukocytes were defined as those cells that remained stationary for at least 30 s within a 100-µm vessel segment. Extravasated leukocytes were those cells in the perivenular tissue within a distance of 50 µm above or below the 100 µm vessel segment under study. In each animal, four to nine vessel segments and three to four vessels were quantified and averages were taken. In selected experiments, total and differential leukocyte counts were performed by staining blood samples taken from the tail vein by Kimura or May-Grunwald/Giemsa stains, respectively. Erythrocyte centreline velocity was determined in some experiments, using an optical doppler velocimeter (Microcirculation Research Institute, College Station, TX), and blood pressure measurements were determined using an electronic pressure transducer (Harvard Apparatus, Millis, MA).
Immunostaining of cremasteric tissue
At the end of selected experiments above, cremaster muscles were dissected away from the animal and fixed in 4% paraformaldehyde (PF). Tissues were blocked and permeabilized in phosphate-buffered saline (PBS) using 20% horse serum and 0.5% Triton X-100, respectively, followed by incubation with the primary mAb, anti-6 mAb GoH3, or a control IgG at 4°C for 24–48 h. After several washes with PBS, an Alexa Fluor 488-conjugated secondary antibody (Molecular Probes, Eugene, OR) was added for 3 h at room temperature. Samples were washed again and viewed using a Zeiss LSM 5 PASCAL confocal laser-scanning microscope (using a x40 water-immersion Achroplan objective with a numerical aperture of 0.75) equipped with an Argon (excitation wavelength: 488 nm) laser. Multiple optical sections of tissue samples were captured and imaged.
Quantification of leukocyte migration into the peritoneal cavity
Mice were injected i.v. with saline, mAb GoH3, or control antibody (all at 3 mg/kg), 15 min before i.p. administration of IL-1ß or TNF- (10 ng or 100 ng, respectively, in 1 ml saline/cavity). Control mice were injected with i.p. saline. Animals were killed by asphyxiation with CO2 4 h later. Peritoneal cavities were opened and lavaged with 3 ml modified PBS solution (containing 0.25% bovine serum albumin and 2 mM EDTA). Total and differential counts of infiltrating leukocytes were determined as detailed above.
Statistics
All results are expressed as mean ± SEM. Statistical significance was assessed by one-way ANOVA with Neuman-Keuls multiple comparison test. Where two variables were analyzed, a Students t-test was used. P < 0.05 was considered significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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6 integrins in neutrophil migration induced by IL-1ß and TNF- in vivo6 integrin-blocking mAb GoH3 [21
] was used to investigate the role of this molecule in leukocyte migration induced by the cytokines IL-1ß and TNF- in vivo. For this purpose, two murine in vivo models were used: leukocyte migration through cremasteric venules, as observed by intravital microscopy, and leukocyte migration into the peritoneal cavity. In both models, leukocyte migration was quantified using a 4-h in vivo test period, a time-frame in which we have previously demonstrated that the profile of leukocyte migration elicited by the cytokines IL-1ß and TNF- is largely neutrophilic [10
, 19
].
In the cremaster muscle model, local administration of IL-1ß (30 ng) or TNF- (300 ng) induced leukocyte firm adhesion and transmigration, which were significantly greater than responses obtained in mice injected with i.s. saline. Pretreatment of mice with the anti-6 integrin mAb GoH3 (3 mg/kg, i.v.) significantly suppressed leukocyte transmigration but not firm adhesion induced by IL-1ß as compared with mice treated with a control mAb (Fig. 1
). In contrast, GoH3 had no effect on leukocyte transmigration induced by TNF-. Similar cytokine-specific profiles of results were obtained in the peritonitis model in that i.v. administration of GoH3 (but not a control mAb) inhibited neutrophil migration into the peritoneal cavity of mice treated with local administration of IL-1ß (10 ng/cavity) but not TNF- (100 ng/cavity; Fig. 2
).
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6 integrins on IL-1ß- and TNF--induced transmigrated neutrophils6 integrins on transmigrated neutrophils induced by IL-1ß and TNF-. For this purpose, in the cremaster muscle model, at the end of the 4-h in vivo test period, saline- or cytokine-stimulated tissues were dissected away from the animal, fixed and immunostained indirectly using mAb GoH3 as detailed in Materials and Methods. The tissues were then analyzed using a confocal laser-scanning microscope. Figure 3
shows examples of images obtained, demonstrating that endothelial cells and leukocytes express 6 integrins, although the expression patterns on transmigrated leukocytes were different in tissues stimulated with IL-1ß or TNF-. In IL-1ß-stimulated (Fig. 3A)
tissues, but not TNF--stimulated tissues (Fig. 3B)
, transmigrated leukocytes exhibited a ring-like expression profile of 6 integrins, indicative of a cell-surface expression profile. These results are in agreement with findings obtained from the peritonitis model, where surface expression of 6 integrins was measured on blood and transmigrated peritoneal neutrophils, as quantified using indirect immunofluorescence and flow cytometry (Fig. 3C)
. Although blood neutrophils exhibited a low level of 6ß1, IL-1ß-induced transmigrated neutrophils exhibited a significantly enhanced level (approximately fourfold increase). Such increased expression of 6ß1 on transmigrated neutrophils was not, however, observed when TNF- was used as the inflammatory stimulus. In contrast to the divergent expression profile of 6ß1 on transmigrated neutrophils in animals injected with IL-1ß and TNF-, in both groups of mice, expression of L-selectin was reduced by 
85% on peritoneal neutrophils as compared with blood cells, and the expression of ß2 integrins was enhanced (data not shown).
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6 integrins in neutrophil transmigration induced by LPS in vivo6 integrins in leukocyte migration when cytokines were applied exogenously, we next investigated the role of this integrin in leukocyte migration under conditions of endogenous cytokine generation. For this purpose, the response induced by locally administered LPS was investigated in the cremaster muscle. Initial and preliminary experiments characterized the dose-response and time-course profile of LPS-induced leukocyte migration in this model. Two i.s. doses of LPS were investigated, 3 µg/site and 30 µg/site, using a 4-h in vivo test period. As the higher dose gave significant and reproducible leukocyte firm adhesion and transmigration responses, 30 µg/site was used in all subsequent experiments. Time-course experiments indicated that although no significant transmigration occurred at a 2-h in vivo test period, this response was significantly elevated above levels detected in saline-injected mice at 4 h and 24 h (data not shown). Although the response at 24 h was greater than that detected at 4 h, the 4-h time-point was selected for all subsequent experiments to maintain consistency with the test periods used when using exogenous cytokines.
The anti-6 integrin mAb GoH3 induced a small but nonsignificant reduction in LPS-induced leukocyte transmigration in the cremaster muscle (Fig. 4
). As this may have been a result of the existence of 6 integrin-independent pathways in the LPS reaction, e.g., mediated by endogenously generated TNF-, the functional roles of TNF- and IL-1ß in LPS-induced leukocyte migration in the cremaster muscle were investigated using the specific blockers, soluble TNF- p55 (p55) receptor fusion protein [22
] and rIL-1ra [23
], respectively. The inhibitors were coinjected with LPS i.s. at concentrations, which in parallel experiments, were shown to inhibit specifically and significantly responses induced by the respective cytokines (data not shown). When tested against LPS-induced leukocyte migration, rIL-1ra and p55 partially suppressed leukocyte adhesion and transmigration (Fig. 5
). Furthermore, preliminary experiments indicated that coinjection of rIL-1ra and p55 with LPS resulted in almost total inhibition of LPS-induced leukocyte transmigration (87% inhibition, n=2 mice).
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in LPS-induced leukocyte migration, an additional series of experiments was conducted to investigate whether under conditions of TNF- blockade, GoH3 could exhibit a greater level of inhibition of LPS-induced leukocyte migration. In these studies, coinjection of p55 with LPS again induced an inhibition of leukocyte transmigration (51.4% inhibition, P<0.05; Fig. 6
). However, injection of mAb GoH3 (3 mg/kg, i.v.), which by itself failed to induce a significant inhibitory effect on LPS-induced transmigration (Fig. 4)
15 min prior to i.s. injection of LPS and soluble p55, led to a greater level of inhibition of leukocyte transmigration (83% inhibition, P<0.001). In contrast, injection of mAb GoH3 to mice injected with LPS and IL-1ra failed to exert a significantly greater level of inhibition than that observed in mice injected with LPS and IL-1ra alone (Fig. 6)
.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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6ß1 supports interaction of neutrophils with laminin-coated plates in vitro [13
, 17
, 18
] and neutrophil migration through the PBM of venules stimulated with IL-1ß in vivo [19
]. Furthermore, the role of this integrin in mediating neutrophil migration through the PBM appears to be associated with PECAM-1-mediated up-regulation of 6ß1 on transmigrated neutrophils. As PECAM-1-deficient mice demonstrated that PECAM-1 mediates leukocyte transmigration through IL-1ß- but not TNF--stimulated murine cremasteric venules [10
], the aim of the present study was to investigate whether the functional role of 6ß1 in leukocyte transmigration exhibited a similar profile of cytokine specificity. Indeed, the findings demonstrate that in line with our observations with PECAM-1, 6ß1-mediated leukocyte transmigration is cytokine-specific, providing further evidence supporting a cooperative interaction between PECAM-1 and 6ß1 in regulation of leukocyte migration through the PBM.
The role of 6ß1 in neutrophil migration was investigated by testing the effect of the blocking anti-6 integrin mAb GoH3 [21
] in two in vivo models, namely, leukocyte migration through mouse cremasteric venules, as observed by intravital microscopy in real-time, and leukocyte migration into stimulated mouse peritoneal cavities. In both models, IL-1ß and TNF- induced significant leukocyte migration, which was predominantly neutrophilic within the 4-h in vivo test periods used. In the cremaster muscle, in agreement with our previous findings [19
], GoH3 significantly inhibited leukocyte transmigration but not firm adhesion induced by IL-1ß. A similar inhibitory effect on IL-1ß-induced neutrophil transmigration was also observed in the peritonitis model. In contrast, however, GoH3 had no inhibitory effects on neutrophil migration in these models when TNF- was used as the inflammatory stimulus. In considering the potential reason behind this stimulus-specific inhibitory effect of GoH3, we hypothesized that the efficacy of the blocking mAb may be related to the expression of 6ß1 on emigrated leukocytes as elicited by IL-1ß or TNF-. To address this, the expression of 6ß1 on blood and transmigrated leukocytes in response to the two cytokines was investigated.
Expression of 6ß1 on transmigrated neutrophils in the cremaster muscle and peritonitis model was investigated by indirect immunofluorescent staining (using mAb GoH3) and analysis by confocal microscopy or flow cytometry, respectively. In both models, evidence was obtained for increased cell-surface expression of 6ß1 on transmigrated neutrophils as compared with blood neutrophils in response to IL-1ß but not TNF-. These results suggest that unlike IL-1ß, TNF--induced transmigration does not regulate neutrophil cell-surface expression of this integrin. Hence, as we have previously shown that TNF--induced neutrophil transmigration is PECAM-1-independent, the findings of the present study indicate that under conditions where PECAM-1 is not functionally important in leukocyte migration, the response also appears to be independent of 6ß1. Collectively, the results presented here in conjunction with our previous observations [10
, 19
] further support the concept that PECAM-1–PECAM-1 interaction at endothelial cell junctions mediates up-regulation of 6ß1 on transmigrated leukocytes, a response that supports leukocyte migration through the PBM.
The molecular basis of PECAM-1- and 6ß1-independent pathways is at present unclear but may well be linked to the ability of the inflammatory trigger to directly stimulate leukocytes and thus activate alternative mechanisms involved in leukocyte transmigration. In support of this, neutrophil migration through rat mesenteric venules induced by the chemoattractant formyl-Met-Leu-Phe (fMLP) is PECAM-1-independent [8
], and fMLP does not enhance surface expression of 6ß1 on the cell surface of mouse neutrophils [17
]. Hence, it is conceptually possible that in the present study, within the models used, TNF- may act predominantly as a direct neutrophil stimulant, thus inducing neutrophil transmigration via adhesive pathways involving key leukocyte adhesion molecules such as ß2 integrins, possibly in conjunction with induced, cell-associated leukocyte proteases. In line with this possibility, although a 4-h treatment with TNF- is known to induce de novo synthesis and increased expression of a number of endothelial cell adhesion molecules such as E-selectin, ICAM-1, and vascular cell adhesion molecule-1 [24
25
26
], we have previously found that leukocyte transmigration in TNF--treated cremaster muscle venules is protein synthesis-independent [27
]. It is interesting that in the same study, leukocyte transmigration induced by IL-1ß was found to be protein synthesis-dependent [27
]. Furthermore, numerous other lines of evidence indicate that TNF- can act in a similar manner to neutrophil chemoattractants in eliciting neutrophil stimulation in vitro and neutrophil migration in vivo. In vitro, TNF- can induce human neutrophil degranulation and generation of superoxide anions from adherent leukocytes [28
] and stimulate rapid adhesion of mouse and human neutrophils [10
, 29
] as well as stimulate the shedding of L-selectin and up-regulation of ß2 integrins in mouse neutrophils [27
]. In vivo, TNF- can stimulate rapid and lymphocyte function-associated antigen-1-dependent leukocyte firm adhesion and transmigration [30
31
32
], which as already discussed, is not inhibited in PECAM-1-deficient mice [10
]. None of the above has been reported for IL-1ß. Collectively, the results suggest that within the protocols used, the 6ß1-independent profile of TNF--induced leukocyte transmigration is as a result of a more dominant role for molecular interactions, which are activated/expressed following direct stimulation of neutrophils by TNF- as opposed to activation of endothelial cell-dependent PECAM-1-mediated events.
In a final series of experiments, the role of 6ß1 in leukocyte transmigration induced by endogenously generated cytokines, as elicited by locally administered LPS, was also investigated. Locally administered LPS induced leukocyte firm adhesion and transmigration in mouse cremaster muscle venules, a response that was only marginally suppressed by the anti-6 integrin mAb GoH3. We hypothesized that the lack of significant effect of this reagent on LPS-induced transmigration may be a result of the generation of stimuli that act in an 6ß1-independent manner. Indeed, using the pharmacological blockers soluble TNF- p55 receptor and rIL-1ra, we found evidence for the involvement of TNF- and IL-1, respectively, in LPS-induced leukocyte migration in agreement with other models [33
]. Blockade of both TNF- receptor and IL-1r resulted in almost total inhibition of the LPS-induced transmigration. As TNF--induced leukocyte transmigration is independent of 6ß1, we next investigated the effect of mAb GoH3 under conditions of TNF- blockade. Hence, although GoH3 had no significant effect on LPS-induced leukocyte transmigration when administered alone, in conjunction with soluble TNF- p55 receptor, it inhibited LPS-induced leukocyte transmigration by 83%, a level of inhibition significantly greater than that observed with the soluble TNF- p55 receptor alone (51% inhibition). In contrast, under conditions of IL-1r blockade, administration of mAb GoH3 failed to exert a greater inhibition of LPS-induced transmigration than that observed with IL-1ra alone. These results support the findings detailed above by demonstrating that in addition to mediating cytokine-specific leukocyte transmigration when the stimuli are applied exogenously, 6ß1 exhibits cytokine-specific leukocyte transmigration as induced by endogenous mediators, i.e., regulating leukocyte transmigration as induced by endogenous IL-1ß but not TNF-.
In summary, although neutrophil migration through the PBM of IL-1ß-stimulated venules is mediated via PECAM-1 and the integrin 6ß1, TNF- mediates neutrophil migration via mechanisms independent of these adhesion molecules. The nature of these mechanisms is currently under investigation in our laboratory.
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ACKNOWLEDGEMENTS |
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Received July 26, 2004; revised September 15, 2004; accepted October 6, 2004.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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6ß1 integrin J. Leukoc. Biol. 61,397-407[Abstract]
6 integrin distribution in human embryonic and adult tissues Histochemistry 101,41-49[CrossRef][Medline]
6ß1 integrin J. Cell Biol. 110,2167-21744ß1
1) J. Immunol. 165,5831-58386ß1 on transmigrated neutrophils in vivo and plays a functional role in the ability of 6 integrins to mediate leukocyte migration through the perivascular basement membrane J. Exp. Med. 196,1201-1211-induced eosinophil accumulation in rat skin is dependent on 4 integrin/vascular cell adhesion molecule-1 adhesion pathways Blood 90,4144-4152 in mouse cremasteric venules Br. J. Pharmacol. 137,1237-1246[CrossRef][Medline]
-induced leukocyte adhesion in venules Br. J. Haematol. 110,424-429[CrossRef][Medline]
, TNF-, IFN- and C5a utilizes LFA-1, Mac-1, and VLA-4 J. Immunol. 154,6533-6540[Abstract]
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