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(Journal of Leukocyte Biology. 2000;68:621-626.)
© 2000 by Society for Leukocyte Biology

Linomide abolishes leukocyte adhesion and extravascular recruitment induced by tumor necrosis factor {alpha} in vivo

Xiao Wei Zhang*, Gunnar Hedlund{dagger}, Per Borgström{ddagger}, Karl E. Arfors{ddagger} and Henrik Thorlacius*

* Department of Surgery, Malmö University Hospital, Lund University, Malmö;
{dagger} Active Biotech Research, Lund, Sweden; and
{ddagger} Sidney Kimmel Cancer Center, La Jolla, California

Correspondence: Henrik Thorlacius, Department of Surgery, Malmö University Hospital, Lund University, 20502 Malmö, Sweden.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The immunomodulator Linomide (roquinimex) ameliorates the development of numerous inflammatory and immunological diseases, including sepsis, arthritis, and encephalomyelitis. However, the mechanism underlying this protective effect of Linomide remains unclear. In this study, we wanted to evaluate the effect of Linomide treatment on the different steps in the extravasation process of leukocytes stimulated by tumor necrosis factor {alpha} (TNF-{alpha}) in vivo. For this purpose, we used intravital microscopy in the mouse cremaster muscle microcirculation. We found that pretreatment with Linomide dose-dependently (3–300 mg/kg) reduced TNF-{alpha}-induced leukocyte adhesion and tissue recruitment. Notably, at 300 mg/kg of Linomide, the leukocyte response to TNF-{alpha} was nearly abolished, i.e. leukocyte adhesion was decreased by 83% and recruitment by 86%. In fact, the anti-inflammatory effect of this dose of Linomide corresponded in magnitude to the potency of 10 mg/kg of dexamethasone. Moreover, administration of Linomide did not alter the systemic leukocyte counts. On the other hand, 1–10 mg/kg of dexamethasone decreased the circulating number of mononuclear leukocytes by 77%. Taken together, our novel findings demonstrate that Linomide is a potent inhibitor of leukocyte adhesion and recruitment in cytokine-activated tissues. These data may help explain the documented protection provided by Linomide in inflammatory diseases characterized by cytokine activation and leukocyte accumulation.

Key Words: dexamethasone • microcirculation • P-selectin • rolling


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Linomide, a quinoline 3-carboxamide (roquinimex), is an immunomodulatory drug, which has been demonstrated to prevent the induction of septic death, systemic lupus erythematosus, arthritis, encephalomyelitis, and diabetes mellitus [1 2 3 4 5 ]. However, the protective mechanism underlying the beneficial effect of Linomide remains to be defined. It is interesting to note that it has been documented in models of experimental encephalomyelitis that Linomide suppresses the up-regulation of tumor necrosis factor {alpha} (TNF-{alpha}) and concomitantly increases the expression of anti-inflammatory cytokines, including transforming growth factor ß (TGF-ß) and interleukin-10 (IL-10), both locally and in peripheral leukocytes [4 , 6 ]. TNF-{alpha} is a pleotrophic peptide, which has been suggested to play a fundamental role in several inflammatory conditions, including rheumatoid arthritis, ulcerative colitis, autoimmune diseases, and surgical injury [7 8 9 ]. The inflammatory reaction is characterized by tissue accumulation of plasma proteins and leukocytes. Leukocyte recruitment is mediated by a coordinated expression of specific adhesion molecules, such as selectins and integrins, which orchestrate the interactions between leukocytes and endothelial cells in the microcirculation [10 , 11 ]. TNF-{alpha}-stimulated leukocyte rolling is considered to be principally mediated by P-selectin [12 , 13 ], although E-selectin and intercellular adhesion molecule-1 (ICAM-1) may contribute to some extent [14 15 16 ]. This rolling adhesive interaction is a precondition for the subsequent firm adhesion and transmigration of leukocytes in vivo [17 ]. Leukocyte rolling reduces the velocity of the circulating leukocytes and this reduction may be important to allow time for these cells to detect chemotactic signals from the local environment and the endothelial surface [18 ]. On the other hand, firm adhesion and transendothelial migration of leukocytes have been reported to be primarily mediated by ß1- and ß2-integrins on leukocytes, which bind to members of the immunoglobulin gene superfamily, such as ICAM-1 and vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells [19 , 20 ] and thereby promoting strong adhesive interaction and arrest of rolling cells.

The objective of this study was to examine the effect of Linomide on cytokine-induced leukocyte rolling, firm adhesion, and tissue accumulation and compare the potential effect of Linomide to treatment with dexamethasone. For this purpose, we used intravital microscopy in the mouse cremaster muscle stimulated with TNF-{alpha}.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Treatment of animals and preparation of the mouse cremaster muscle
Male NMRI mice weighing ~23–28 g were maintained on 12-h dark and 12-h light cycles and given food and water ad libitum. Linomide (Active Biotech Research, Lund, Sweden; Fig. 1 ) was supplied in the drinking water (10, 100, 1000 mg/L, pH adjusted to 7.0–7.4) for 3 days, and average intake was 3, 30, and 300 mg/kg/day. The standard protocol for administration of Linomide is 2–4 days pretreatment [1 , 2 ]. Mice were anesthetized with 7.5 mg ketamine hydrochloride (Hoffman-La Roche, Basel, Switzerland) and 2.5 mg xylazine (Janssen Pharmaceutica, Beerse, Belgium) per 100 g body weight intraperitoneally (i.p.) and the cremaster muscle was prepared for intravital microscopy as described earlier [21 ]. In brief, a midline incision of the skin and fascia was made over the ventral aspect of the left scrotum and the incised tissues were retracted to expose the cremaster muscle sack. The cremaster muscle was then separated from the epididymis, and the testis was pushed back to the side of the preparation. The preparation was performed on a transparent pedestal to allow transillumination and microscopic observation of the cremaster muscle microcirculation. Great care was taken to avoid any bleeding from the margins of the cremaster muscle by using electrocautery. Throughout the preparation and experiment the exposed tissue was covered with a plastic membrane to prevent the tissue from drying. Intrascrotal injection of 0.5 µg of rat recombinant TNF-{alpha} (R & D Systems Europe, Abingdon, Oxon, UK) in 0.15 mL phosphate-buffered saline (PBS) was performed 2–3 h before microscopic observation. This dose of TNF-{alpha} is commonly used in the cremaster muscle to induce a reproducible leukocyte response [14 , 18 ]. In separate experiments, mice were pretreated (i.p.) with 1 or 10 mg/kg of dexamethasone (Decadron, Merck Sharp & Dohme, Haarlem, The Netherlands) for 2 h before administration of TNF-{alpha}. Blood samples were taken from the tail artery after the experiment for analysis of systemic leukocyte counts.



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  		Figure 1. Structure of Linomide. The molecular weight of Linomide is 308.3 g/mol and the chemical name is N-methyl-N-phenyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide.

 
Intravital microscopy
Observations of the cremaster microcirculation were made using an Olympus microscope (BX50WI, Olympus Optical, Hamburg, Germany) equipped with water immersion lenses (x40/NA 0.75 and x63/NA 0.90). The microscopic image was televised (Sony Triniton) using a charge-coupled device video camera (FK 6990 Cohu, Pieper, Berlin, Germany) and recorded on videotape (Panasonic SVT-S3000 S-VHS recorder) for subsequent off-line analysis. After positioning under the microscope, a 10-min equilibration period preceded quantitative measurements. Analysis of leukocyte flux and leukocyte-endothelium interactions (rolling and adhesion) was made in venules (inner diameter 20–40 µm) with stable resting blood flow. Rolling leukocyte flux was determined at indicated time points by counting the number of rolling leukocytes passing a reference point in the microvessel per 30 s and expressed as cells per minute. Leukocyte adhesion in venules (stationary for >30 s) was counted along 200- to 380-µm-long segments of the endothelial lining on one side of the vessel lumen and expressed as number of adherent cells per millimeter. In separate experiments, red blood cell velocity was measured on-line by the use of an optical Doppler velocimeter (Microcirculation Research Institute, Texas A & M University, College Station, TX). Venular wall shear rate was determined based on the Newtonian definition: wall shear rate = 8 [(red blood cell velocity/1.6)/venular diameter] as described previously [22 ].

Histology
Samples of intact cremaster muscle microvascular networks were fixed in 4% formaldehyde overnight and then stained with Giemsa for 1 h. After differentiation in acetic acid (0.01%), the samples were mounted on gelatin (1%)-precoated glass slides and covered with a coverglass by applying DPX after drying as previously described in detail for the rat mesentery [23 ]. The ratio of intravascular polymorphonuclear (PMNL) and mononuclear (MNL) leukocytes was based on analysis in venules (inner diameter 20–50 µm) with a mean value of two to six vessels in each animal. Leukocyte emigration was quantified by counting the number of extravascular PMNLs and MNLs per high-power field observed along a randomly selected venule in each preparation and expressed as number of cells per square millimeter. The number of intact and degranulated mast cells were counted and expressed as the percentage degranulated cells.

Reverse transcriptase-polymerase chain reaction (RT-PCR)
Total RNA was extracted from the cremaster muscle using an acid guanidinium-phenol-chloroform method (TRIzol Reagent; GIBCO-BRL Life Technologies, Grand Island, NY) and treated with RNase-free DNase (DNase I; Amersham Pharmacia Biotech, Uppsala, Sweden) in order to remove potential genomic DNA contaminants according to the manufacturer’s protocol. RNA concentrations were determined by measuring the absorbance at 260 nm spectrophotometrically. RT-PCR was performed with SuperScrip One-Step RT-PCR system (GIBCO-BRL Life Technologies). Each reaction contained 250 ng of cellular total RNA as a template and 0.2 µM of each primer in a final volume of 50 µL. Mouse ß-actin served as a housekeeping gene. The RT-PCR profile was 1 cycle of cDNA synthesis at 50°C for 30 min, 94°C for 2 min, followed by 35 cycles of denaturation at 94°C for 30 s, annealing at 55°C for 30 s, and extension at 72°C for 1 min, 1 cycle of final extension at 72°C for 10 min. After RT-PCR, aliquots of the RT-PCR products were separated on a 2% agarose gel containing ethidium bromide and photographed. The primers sequences of P-selectin and ß-actin were as follows: P-selectin (f) 5’-ACG AGC TGG ACG GAC CCG-3’, P-selectin (r) 5’-GGC TGG CAC TCA AAT TTA CAG-3’; ß-actin (f) 5’-ATG TTT GAG ACC TTC AAC ACC-3’, ß-actin (r) 5’-TCT CCA GGG AGG AAG AGG AT-3’.

Statistical analysis
Statistical evaluations were performed using Krushal-Wallis one-way ANOVA on Ranks (Dunn’s method) for unpaired samples. The results are presented as mean values ± SEM. Unless stated otherwise, n represents number of animals.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Ten minutes after surgical preparation for intravital microscopy, it was found in mice treated with PBS intrascrotally (i.s.) that the number of leukocyte rolling, adhesion, and extravasation of leukocytes was 51 ± 7 cells/min, 28 ± 3 cells/mm, and 131 ± 9 cells/mm2, respectively. Intrascrotal administration of TNF-{alpha} (0.5 µg) for 2–3 h increased the number of adherent and extravascular leukocytes to 176 ± 4 cells/mm (Fig. 2B , P < 0.05 vs. intrascrotal PBS) and 991 ± 50 cells/mm2 (Fig. 2C , P < 0.05 vs. intrascrotal PBS), respectively. Rolling leukocyte flux in response to TNF-{alpha} challenge was 33 ± 5 cells/min, which was not significantly different from control treatment (Fig. 2A , P > 0.05 vs. intrascrotal PBS). We found that Linomide dose-dependently reduced TNF-{alpha}-induced leukocyte adhesion and extravascular recruitment (Fig. 2B and 2C , P < 0.05 vs. PBS). Strikingly, administration of 300 mg/kg Linomide significantly decreased the number of adherent and tissue leukocytes by 83 and 86%, respectively. This reduced TNF-{alpha}-stimulated leukocyte response was similar in magnitude to that exerted by 10 mg/kg of dexamethasone (Fig. 2B and 2C) . Dexamethasone (10 mg/kg) reduced leukocyte adhesion by 81% and recruitment by 79% (Fig. 2B and 2C) . Linomide had some inhibitory effect on leukocyte rolling in the TNF-{alpha} activated tissue (Fig. 2A) . Figure 3 summarizes this set of experiments, which demonstrates the different susceptibility of TNF-{alpha}-induced leukocyte adhesion and emigration to the inhibitory action of Linomide. The calculated ED50 of Linomide on leukocyte adhesion and extravascular recruitment was in both cases close to 100 µmol/kg (Fig. 3A) , suggesting that the inhibitory action of Linomide on tissue accumulation was mainly due to interference with firm leukocyte adhesion. The ED50 of dexamethasone on leukocyte adhesion and extravasation was found to be ~1 µmol/kg (Fig. 3B) .



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  		Figure 2. Effect of Linomide (Lin, 3, 30, and 300 mg/kg) and dexamethasone (Dex, 1 and 10 mg/kg) pretreatment on TNF-{alpha}-induced leukocyte (A) rolling, (B) adhesion, and (C) emigration. Emigrated leukocytes (Total) were subtyped into polymorphonuclear (PMNL) or mononuclear (MNL) leukocytes. Data represent mean ± SEM. Asterisks indicate significant difference (P < 0.05 vs. PBS + TNF, n = 5–8).

 


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  		Figure 3. Different susceptibility of TNF-{alpha}-induced leukocyte adhesion and emigration to the inhibitory effect of Linomide. The (A) Linomide and (B) dexamethasone doses producing a 50% inhibition (ED50) for adhesion and emigration were estimated to 100 and 1 µmol/kg, respectively (n = 5–8).

 
It is important to note, we observed that administration of Linomide (3, 30, and 300 mg/kg) did not reduce systemic PMNL and MNL counts (Table 1 ). However, on the other hand, we found that 1 and 10 mg/kg of dexamethasone decreased the number of circulating MNL by 74 and 77%, respectively (Table 1 , P < 0.05 vs. control), whereas the level of polymorphonuclear cells was not changed (Table 1) .


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  		Table 1. Systemic Leukocyte Counts

 
Histological analysis of Giemsa-stained whole-mounts of cremaster muscle preparations revealed that more than 76% of the leukocytes in the venules and the extravascular space were polymorphonuclear leukocytes and less than 24% were mononuclear leukocytes in all groups (Table 2 ). Moreover, the percentage of mast cell degranulation was 2–3% in all groups (not shown). Hemodynamic parameters were similar in all experimental groups (Table 3 ).


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  		Table 2. Percentage of PMNL and MNL in Venules and in the Extravascular Space

 

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  		Table 3. Hemodynamic Parameters in Venules of the Cremaster Muscle

 
Total RNA was isolated, reverse transcribed into cDNA, and PCR amplified with specific primers for P-selectin. In control mice, a detectable but relatively weak baseline expression of P-selectin mRNA was observed (Fig. 4 ). It was found that 3-h stimulation with TNF-{alpha} (0.5 µg) increased the expression of P-selectin mRNA in the cremaster muscle (Fig. 4) . Pretreatment with Linomide (3, 30, and 300 mg/kg) for 3 days had no apparent effect on the TNF-{alpha}-induced gene transcription of P-selectin mRNA (Fig. 4) .



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  		Figure 4. Expression of P-selectin mRNA in the mouse cremaster muscle. TNF-{alpha} (TNF, 0.5 µg) was injected intrascrotally 3 h before harvesting of the cremaster muscle for RT-PCR analysis. PBS-treated animals served as negative control (Control). In separate experiments, the animals were pretreated with Linomide (Lin, 3, 30, and 300 mg/kg) for 3 days before TNF-{alpha} challenge. ß-actin served as a housekeeping gene. Results presented are from one experiment, which is representative of four others performed.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Linomide has been shown to suppress the development of a broad spectrum of autoimmune and inflammatory diseases [1 2 3 4 5 6 ]. However, the beneficial mechanism behind the action of Linomide remains to be documented. In this study, we demonstrate that treatment with Linomide abolishes the leukocyte response to TNF-{alpha} in vivo. It was observed that Linomide markedly inhibited TNF-{alpha}-induced firm leukocyte adhesion and tissue infiltration. In addition, the anti-inflammatory potency of Linomide was found to be similar in magnitude as that of a high dose of dexamethasone. Thus, our findings may contribute to the understanding of the beneficial effect of Linomide observed in pathological inflammation and autoimmune diseases characterized by TNF-{alpha} activation.

Although it has been demonstrated that Linomide inhibits the expression and production of proinflammatory cytokines, including TNF-{alpha}, IL-ß, and interferon-{gamma} from activated macrophages and lymphocytes [2 , 4 , 6 ], the effect of Linomide on cytokine-induced inflammation has not been investigated. The extravasation process of leukocytes into tissue is a multistep process where leukocyte rolling is a precondition for the subsequent firm adhesion and transendothelial migration [17 ]. Several studies have shown that late (2–4 h) leukocyte rolling induced by TNF-{alpha}, bacterial, and allergic antigens is predominately mediated by P-selectin [12 , 13 ], and firm adhesion and transmigration is provided by ß1- and ß2-integrins [10 , 24 ]. This study demonstrates for the first time that Linomide treatment dose-dependently inhibits leukocyte recruitment in response to TNF-{alpha} stimulation in vivo. The reduction in TNF-{alpha}-induced leukocyte accumulation was found to be due to a substantial inhibition of stable leukocyte adhesion, whereas leukocyte rolling was only slightly affected by Linomide. In line with these observations, we found that Linomide did not alter the mRNA expression of P-selectin in the cremaster muscle after exposure to TNF-{alpha}. The mechanism of Linomide’s effect on the firm adhesive interaction of leukocytes to the cytokine-activated endothelium is presently not known, although it can be speculated that the previously reported increase in TGF-ß and IL-10 expression observed after Linomide administration may be involved in this anti-adhesive effect [4 , 6 ]. In fact, TGF-ß and IL-10 have been shown to inhibit leukocyte adhesion and transmigration of leukocytes provoked by cytokines and lipopolysaccharide [25 , 26 ]. Moreover, it can not be excluded that Linomide interferes with the expression and/or function of adhesion molecules on leukocytes or endothelial cells. It is important to note that Linomide treatment did not change the number of circulating leukocytes, excluding the possibility that the inhibition of leukocyte recruitment was due to leukopenia. TNF-{alpha} has been implicated as an important regulator of inflammatory processes and immunological surveillance and may play a fundamental role in the pathogenesis of numerous diseases dominated by leukocyte recruitment and activation. Our novel findings suggest that Linomide markedly inhibits the leukocyte response in TNF-{alpha}-activated tissues and may thus provide a partial explanation of the protective effect of Linomide documented in endotoxemia and inflammatory disease processes in the kidneys, joints, and nervous system [1 2 3 4 ]. We found that the extent of leukocyte adhesion and emigration was similarly inhibited by Linomide, i.e. the calculated ED50 value was 100 µmol/kg for both adhesion and emigration, suggesting that Linomide predominantly reduced TNF-{alpha}-induced leukocyte adhesion, whereas the transmigration process per se was not disturbed.

In this investigation, we also compared the anti-inflammatory effects of Linomide to those of glucocorticoids, which constitute a common therapy in inflammatory conditions. These potent anti-inflammatory agents, including dexamethasone, have been shown to effectively inhibit leukocyte recruitment [27 ]. We found that dexamethasone treatment markedly and dose-dependently reduced TNF-{alpha}-induced leukocyte adhesion and extravascular recruitment. Notably, the ED50 of dexamethasone on leukocyte adhesion and extravasation was 1 µmol/kg, which is 100 times lower than that of Linomide. That dexamethasone inhibits firm adhesion of leukocytes to the endothelium is supported by several previous investigations through the use of intravital microscopy [28 , 30 , 31 ]. In fact, we found that the effective dose of dexamethasone was 10 mg/kg, whereas 1 mg/kg had no influence on the leukocyte response to TNF-{alpha}, which is in line with a study by Schneider et al. [28 ]. It can be argued that 10 mg/kg of dexamethasone is a relatively high dose required to inhibit leukocyte accumulation but, in this context, it should be noted that a previous report showed that acute single administration of dexamethasone is four times less effective than repeated application of this steroid during a 5-day period [29 ]. Notably, we observed in the present study that treatment with dexamethasone did not inhibit leukocyte rolling in postcapillary venules activated by TNF-{alpha}, which is in line with a previous study by Tailor et al. [29 ]. This finding is in contrast to that reported by Davenpeck et al. [30 ] reporting that dexamethasone may inhibit the number of rolling leukocytes. The reason for this discrepancy is not known but may be related to the different stimulus used in these studies, i.e. Manculso et al. [31 ] applied lipopolysaccharide, whereas we examined TNF-{alpha} and Tailor et al. studied IL-1ß [29 ]. However, in this context it is interesting to note that Schneider et al. [28 ] also used lipopolysaccharide, although they found that dexamethasone only reduced leukocyte adhesion and extravasation, whereas leukocyte rolling was not changed. One explanation may be related to the dose of LPS, i.e. Schneider applied a 20 times higher dose of LPS than that used in the study by Davenpeck et al. [30 ], suggesting that dexamethasone may inhibit leukocyte rolling in situations of mild inflammation. Nonetheless, the findings presented here and in several previous investigations demonstrate that dexamethasone mainly inhibits firm adhesion and transendothelial migration of leukocytes, whereas the rolling adhesive interaction is not or is only minimally reduced [28 , 29 , 31 ]. This notion suggests that glucocorticoid-reduced leukocyte accumulation in vivo is predominantly mediated by an inhibitory effect on the leukocytes. In spite of the fact that glucocorticoids are known to attenuate leukocyte recruitment, the literature on the detailed mechanisms by which glucocorticoids inhibit tissue accumulation of leukocytes remains complex and partly contradictory. For example, some reports have suggested that glucocorticoids inhibit mediator-induced expression of endothelial adhesion molecules, such as E-selectin and ICAM-1 [32 ], whereas others cannot confirm such findings [33 ] and some report that dexamethasone primarily attenuates the expression of CD18 [30 , 34 ].

In conclusion, this study demonstrates that Linomide effectively inhibits leukocyte adhesion and tissue accumulation induced by TNF-{alpha} in vivo. The anti-inflammatory effect of Linomide on the leukocyte response is comparable to a high dose of exogenous dexamethasone. Our findings expand the understanding of the action of Linomide and may explain the documented protection provided by Linomide in inflammatory and immunological diseases.


   ACKNOWLEDGEMENTS
 
This study was supported by the Swedish Medical Research Council (K2000-04P-13411-01A, K98-27I-11610-03), Cancerfonden (4265-B99-01XAB), Allmäna sjukhusets i Malmö stiftelse för bekämpande av cancer, MAS fonder, the Österlund Foundation, the Tore Nilsson Foundation, the Greta and Johan Kock Foundation, Malmö University Hospital, and Lund University.

Received December 7, 1999; revised April 19, 2000; accepted June 15, 2000.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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R. Schramm and H. Thorlacius
Staphylococcal Enterotoxin B-Induced Acute Inflammation Is Inhibited by Dexamethasone: Important Role of CXC Chemokines KC and Macrophage Inflammatory Protein 2
Infect. Immun., May 1, 2003; 71(5): 2542 - 2547.
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