The Chemokine RANTES Is a Crucial Mediator of the Progression from Acute to Chronic Colitis in the Rat

Maureen N. Ajuebor, Cory M. Hogaboam, Steven L. Kunkel, Amanda E. I. Proudfoot and John L. Wallace
J Immunol January 1, 2001, 166 (1) 552-558; DOI: https://doi.org/10.4049/jimmunol.166.1.552

Abstract

Chemokines have well characterized proinflammatory actions, including the ability to induce extravasation of leukocytes that participate in chronic inflammation. In this study, we evaluated the role of a C-C chemokine, RANTES, in the chronic phase of a rat model of colitis. Colitis was induced by intracolonic administration of trinitrobenzene sulfonic acid. At various timepoints thereafter (2 h to 14 days), colonic tissue levels of several chemokines were measured. Unlike the expression of monocyte chemoattractant protein-1, macrophage inflammatory protein-2, and cytokine-induced neutrophil chemoattractant, the expression of RANTES was significantly elevated during the chronic phase of colitis (≥7 days after induction). Colonic RANTES mRNA expression was also significantly elevated during the chronic phase of colitis. The numbers of macrophages and monocytes in the colonic mucosa increased substantially during the chronic phase, as did expression of two of the receptors (CCR1 and CCR5) to which RANTES is known to bind. Administration on days 7 through 14 after trinitrobenzene sulfonic acid administration of a CCR1/CCR5 receptor antagonist, Met-RANTES, resulted in a significant reduction of both macroscopic and microscopic colonic damage, as well as reducing the recruitment into the colon of monocytes, mast cells, and neutrophils. In some rats, treatment with Met-RANTES resulted in a near-complete resolution of colonic damage and inflammation. These results suggest a crucial role of RANTES in the progression from acute to chronic inflammation in a rat model of colitis.

Chemokines are proinflammatory proteins that participate in immune and inflammatory responses through the chemoattraction and activation of leukocytes (1, 2). Chemokines, a large superfamily of structurally related cytokines, are divided into four subfamilies (C-X-C, C-C, C, and C-X3-C) based on the arrangement of their amino terminal cysteine residues (3, 4). Their biological actions are mediated through a family of seven-transmembrane G protein-coupled receptors (5).

RANTES is a C-C chemokine that promotes the recruitment and activation of inflammatory cells such as monocytes (6), lymphocytes (7), mast cells (8), and eosinophils (9). RANTES is a ligand for the chemokine receptors CCR1, CCR3, and CCR5 (10), and increased expression of RANTES has been observed in vivo in inflammatory diseases such as glomerulonephritis (11, 12), adjuvant-induced arthritis (13), and granulomatous inflammation (14). Of particular relevance to this study is a report of increased expression of RANTES in colonic biopsies from patients with active inflammatory bowel disease (IBD)3 (15). In that study, the expression of RANTES mRNA was found to be increased in biopsies from patients with Crohn’s disease or ulcerative colitis, particularly in intraepithelial lymphocytes and in the subepithelial lamina propria. RANTES expression in animal models of colitis has not been described. Moreover, no interventional studies have been performed to determine whether RANTES makes an important contribution to inflammation and/or injury in human IBD or in experimental colitis.

The purpose of this study was to assess the contribution of RANTES to the pathogenesis of colitis induced in the rat by trinitrobenzene sulfonic acid (TNBS). In particular, we were interested in the possibility that RANTES, through its ability to recruit monocytes and mast cells, may play a role specifically in the chronic phase of colonic inflammation following TNBS administration. Previous studies using this model have documented important roles for a number of inflammatory mediators (e.g., leukotrienes, tachykinins, prostaglandins, IL-1, TNF) in the inflammation and injury occurring during the first week after TNBS administration. Indeed, inflammation during the acute phase could be markedly reduced by a number of drugs that targeted these inflammatory mediators (16, 17, 18, 19, 20, 21). However, modifying the inflammatory response once it has progressed to a more chronic phase has proven to be much more difficult.

Materials and Methods

Animals

Male Wistar rats (175–200 g) were purchased from Charles River Breeding Farms Limited (Montreal, Canada). The rats were fed a standard chow pellet diet, had free access to water, and were maintained on a 12-h light/dark cycle. All procedures in this study were approved by the Animal Care Committee of the University of Calgary and conformed to the guidelines established by the Canadian Council on Animal Care.

Induction of colitis

Rats were lightly anesthetized with halothane, and the hapten TNBS (60 mg/ml in 0.5 ml of 50% ethanol) was administered into the distal colon via a cannula (22). At selected times thereafter (2 h to 14 days), the rats were killed by cervical dislocation. The colon was excised and examined for macroscopic damage by an observer unaware of the treatments. The colonic damage was scored using the criteria outlined in Table I⇓. After examination, tissue samples were taken for determination of tissue chemokine levels and for measurement of RANTES mRNA expression. Age-matched, untreated rats served as controls.

View this table:
Table I.

Criteria for macroscopic scoring of colonic damage

Colonic chemokine expression

Samples of distal colonic tissues were homogenized in 1.5 ml of lysis buffer containing 0.1% Triton X-100, 500 mM NaCl, 50 mM HEPES, 0.1 mg/ml leupeptin, and 10 mg/ml PMSF. The homogenates were incubated on ice for 30 min and then centrifuged (400 × g for 10 min). The supernatants were collected and stored at −80°C until used for determination of chemokine protein levels by ELISA (23) and total protein concentration by colorimetric protein assay (Bio-Rad, Richmond, CA). The chemokines that were measured were RANTES, monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-2, and cytokine-induced neutrophil chemoattractant (CINC).

mRNA expression

RNA was extracted from colonic tissue using Trizol reagent according to the manufacturer’s instructions (Life Technologies, Burlington, Canada). The yield and purity of the RNA was determined spectrophotometrically at 260 and 280 nm. Isolated RNA (2 μg in diethyl pyrocarbonate-treated water) was reverse transcribed to cDNA and amplified by PCR as previously detailed (24). Briefly, DNA amplification was performed under the following conditions: denaturation at 94°C for 1 min, annealing at 55°C for 30 s, and extension at 72°C for 1 min. The RANTES/GAPDH genes were coamplified for 30 and 22 cycles, respectively. The sequences for the RANTES and GAPDH primers used have been described elsewhere (9, 24, 25). To ensure that the amplified PCR product was measured only during the exponential phase of the amplification reaction, the optimum number of PCR cycles was determined for each primer pair. In addition, to exclude the presence of contamination, amplification was always performed in which cDNA was omitted from the PCR mixture. Amplified products were visualized on a 2% agarose gel stained with ethidium bromide, and the size of the PCR product was confirmed with m.w. markers (Life Technologies). The relative quantity of mRNA was estimated by densitometric analysis using Quantity One software (Bio-Rad), normalized to the respective GAPDH, and expressed as a ratio. Data are presented as the mean normalized ratio ± SE.

Expression of mRNA for the chemokine receptors CCR1 and CCR5 was also examined by RT-PCR at various times after induction of colitis, as described above. The primers used for this purpose have been described previously (26).

Effects of Met-RANTES

Met-RANTES is a modified chemokine that binds with high affinity, but does not activate, the chemokine receptors CCR1 and CCR5 (27, 28). Rats were treated with Met-RANTES (40 or 200 μg/rat; i.v.) on day 7 after the administration of TNBS and every 24 h thereafter for 1 wk. Control rats received the vehicle (sterile saline) at the same times. All rats were killed 14 days after TNBS administration for assessment of colonic damage. Additional tissues were taken for analysis of myeloperoxidase (MPO) activity as an index of granulocyte infiltration (17) and for histological examination. Slides were coded to prevent observer bias, and histological sections were then evaluated and scored by an observer unaware of the treatments. The 200-μg dose of Met-RANTES used in this study has been shown to be effective in reducing inflammation in a rodent model of glomerulonephritis (12).

Morphological studies

Colonic tissues were fixed overnight in 10% neutral buffered formalin, dehydrated in graded concentrations of ethanol, embedded in paraffin, and sectioned. Sections (5 μm thick) were stained with hematoxylin and eosin according to standard protocols for histological examination. RANTES has been shown to play a role in the recruitment of mast cells (8) and monocytes (12) into tissues; thus, the effect of treatment with Met-RANTES on the recruitment of these cells into the colon after TNBS administration was determined. For monocyte enumeration, sections were pretreated with 3% hydrogen peroxide in methanol for 10 min to inactivate endogenous peroxidases, followed by permeabilization in PBS containing normal horse serum and Triton X-100 at room temperature for 60 min. Specific labeling of monocytes was performed by incubation of sections overnight at 4°C with anti-ED1 Ab (clone 1C7, 1:10 dilution; PharMingen, Mississauga, Ontario, Canada) to detect mononuclear phagocytes. Sections were then treated with HRP-conjugated secondary Ab (rat anti-mouse IgG; Jackson ImmunoResearch, West Grove, PA) for 90 min at room temperature. The slides were treated with diaminobenzidine for color development and counterstained with hematoxylin. As a negative control, mouse IgG was used.

For mast cell staining, colonic tissues were fixed for 48 h in Carnoy’s fixative (ethanol/chloroform/acetic acid, 6:3:1), processed, and then stained with Alcian blue/safranine (29). Slides were coded to prevent observer bias, and histological sections were then evaluated and scored by an observer unaware of the treatments the rats had received.

Materials

TNBS was obtained from Fluka Chimica (Buchs, Switzerland). RT-PCR reagents were obtained from Amersham Pharmacia Biotech (Piscataway, NJ). Met-RANTES was synthesized by Serono Pharmaceutical Institute (Geneva, Switzerland). All other chemicals were obtained from Sigma (St. Louis, MO) or VWR Scientific (Edmonton, Canada).

Statistical analysis

All data are shown as mean ± SE. Comparisons between two experimental groups of data were performed using Student’s unpaired t test, except in the case of the colonic damage scores, in which a Mann-Whitney U test was used. Comparisons among three or more experimental groups were performed using a one-way ANOVA followed by a Dunnett’s multiple comparison test. Probability values of <5% (p < 0.05) were considered significant.

Results

Consistent with previous reports (17, 30), intracolonic administration of TNBS caused severe ulceration and damage to the distal colon of the rat. The macroscopic damage scores, MPO activities, and expression of chemokines at various times after TNBS administration are summarized in Fig. 1⇓. Over the course of the 2-wk study, there was a gradual decline in the colonic damage score. MPO activity reached a peak at 72 h post-TNBS, and gradually declined thereafter. RANTES expression was not significantly different from controls (i.e., rats without colitis) during the acute phase of colitis (2–72 h post-TNBS). However, RANTES expression was significantly elevated during the period 7–14 days after administration of TNBS, a time when the expression of the other chemokines did not differ significantly from controls. In addition to the changes in chemokine protein expression shown in Fig. 1⇓, we observed that expression of CINC was markedly up-regulated during the acute phase of colitis (2–72 h post-TNBS; peak increase of 20-fold at 4 h), but was not significantly different from controls during the 7- to 14-day post-TNBS period.

FIGURE 1.
FIGURE 1.

Top, Colonic macroscopic damage score and MPO activity at various times after induction of colitis with TNBS. Bottom, Colonic tissue level of RANTES, MCP-1, and MIP-2 at various times after induction of colitis with TNBS. Results are expressed as mean ± SE, with six to eight rats per group. ∗, p < 0.05; ∗∗∗, p < 0.001 vs control (i.e., rats without colitis).

In parallel with the changes in RANTES protein expression, significant increases in RANTES mRNA expression in the colon were seen 7 days (2.6-fold) and 14 days (3.5-fold) after administration of TNBS (Fig. 2⇓).

FIGURE 2.
FIGURE 2.

Colonic expression of RANTES mRNA after induction of colitis with TNBS. Top, Representative mRNA gel. Bottom, Densitometric analysis of RANTES mRNA expression (as a ratio of GAPDH mRNA expression). Results are expressed as mean ± SE, with 6–10 rats per group. ∗∗, p < 0.01 vs control.

Time course of changes in colonic monocyte and mast cell numbers

As summarized in Fig. 3⇓, significant increases in colonic monocyte and mast cell numbers occurred during the period 7–14 days after TNBS administration (i.e., the numbers were significantly elevated at day 14, but not at day 7).

FIGURE 3.
FIGURE 3.

Colonic monocyte and mucosal mast cell numbers at various times after induction of colitis with TNBS. Each column represents the mean ± SE, with six to eight rats per group. ∗∗, p < 0.01 vs the control group (i.e., rats without colitis).

Time course of changes in chemokine receptor expression

The expression of mRNA for the chemokine receptors CCR1 and CCR5 increased significantly following induction of colitis. The ratio of CCR1 to GAPDH mRNA increased from 0.23 ± 0.14 in healthy controls to 1.55 ± 0.19, 1.98 ± 0.07, and 2.32 ± 0.20 at 3, 7, and 14 days after TNBS administration, respectively (p < 0.01 at each of these times). In the case of CCR5, the expression of mRNA as a ratio of GAPDH mRNA expression was not significantly changed at day 3 post-TNBS (1.78 ± 0.09) vs the healthy controls (1.25 ± 0.04). However, at both day 7 and day 14 there was a significant (p < 0.01) increase in expression (2.28 ± 0.10 and 2.81 ± 0.27, respectively).

Effects of Met-RANTES on macroscopic severity of colitis

Treatment with Met-RANTES (200 μg) after the onset of colitis significantly reduced the macroscopic scores for colonic damage (Fig. 4⇓). All rats in the vehicle-treated group exhibited severe damage. In the group treated with Met-RANTES, four of the six rats exhibited little or no colonic damage, whereas the remaining two rats exhibited damage of similar severity to that seen in the controls (Fig. 4⇓).

FIGURE 4.
FIGURE 4.

Effects of Met-RANTES on colonic macroscopic damage score (top) and histological damage score (bottom) in colitic rats. Met-RANTES (200 μg/rat; i.v) or vehicle were administered to rats beginning on day 7 following the induction of colitis and killed on day 14 day post induction of colitis. Each point represents the score for one rat (n = 6 per group). ∗, p < 0.05 vs the vehicle-treated group.

Treatment with a lower dose of Met-RANTES (40 μg/day; n = 5) did not significantly affect the colonic damage score (5.8 ± 0.2 vs 5.6 ± 0.3 in saline-treated controls) or colonic MPO activity (37.7 ± 7.9 vs 32.6 ± 5.0 U/mg in saline-treated controls).

Effects of Met-RANTES on histological severity of colitis

Histological assessment confirmed the significant reduction of tissue injury in rats treated with the higher dose of Met-RANTES (Fig. 4⇑). This histological evaluation confirmed the very low level of damage or inflammation in four of the six rats treated with Met-RANTES, whereas all six rats receiving the vehicle had widespread tissue destruction and massive, transmural inflammation. Examples of the histological appearance of the colonic tissues from rats treated with Met-RANTES or vehicle are shown in Fig. 5⇓. In the vehicle-treated rats, there was widespread destruction of the mucosa with extensive, transmural infiltration of neutrophils, monocytes, and lymphocytes (mastocytosis was also evident in sections stained with Alcian blue/saffranine). In contrast, in the rats treated with Met-RANTES in which a macroscopic response was evident, there was minimal damage to the surface epithelium, and there was mild inflammation of the mucosa (mainly neutrophils), but no transmural inflammation.

FIGURE 5.
FIGURE 5.

Representative histological appearance after Met-RANTES or vehicle treatment in rats with colitis. A, Appearance of colonic tissue from a rat treated with vehicle on days 7 through 14 after induction of colitis with TNBS. Note the extensive inflammatory infiltrate extending transmurally. There is massive thickening of the bowel wall. B–D, Examples of the appearance of colonic tissue from rats treated with Met-RANTES on days 7 through 14 after induction of colitis. B and D, Examples in which the Met-RANTES treatment resulted in almost complete resolution of colitis. The epithelium is intact, and there is only mild inflammation of the mucosa and submucosa. The thickness of the bowel wall is substantially reduced compared with that seen in rats treated with vehicle. C, An example of the appearance of the colon in a rat that did not exhibit resolution of colitis after treatment with Met-RANTES. Transmural inflammation is evident, as well as disruption of the mucosal layer.

Effects of Met-RANTES on cell infiltration

A significant reduction of the numbers of mast cell and monocytes in the colon was seen in rats treated with Met-RANTES (Fig. 6⇓). In addition, a significant reduction in the number of granulocytes, as measured by tissue MPO activity, was observed (Fig. 6⇓).

FIGURE 6.
FIGURE 6.

Effects of Met-RANTES on colonic MPO activity (top), monocyte numbers (middle), and mucosal mast cell numbers (bottom) in rats with colitis. Met-RANTES (200 μg/rat; i.v) or vehicle was administered to rats on days 7 through 14. Dotted lines represents mean levels in healthy controls (n = 4). Each column represents the mean ± SE, with six rats per group. ∗, p < 0.05; ∗∗∗, p < 0.001 vs the vehicle-treated group.

Discussion

In recent years, a number of studies have provided evidence consistent with a role for various chemokines (e.g., IL-8, MCP-1, RANTES) in IBD (15, 30, 31, 32, 33). Specifically, increased expression of these chemokines was observed in colonic tissue from IBD patients vs controls. The extent to which these chemokines contribute to the pathogenesis of IBD is not clear, as interventional studies using inhibitors of chemokine synthesis or antagonists of chemokine receptors have not yet been performed. However, in this study the use of an animal model of colitis has permitted us to determine the time course of expression of a number of chemokines and chemokine receptors, and then to examine the impact on the course of colitis of treatment with a chemokine receptor antagonist. Of four chemokines examined, only the tissue levels of RANTES were significantly elevated during the chronic phase of colitis (i.e., >1 wk after TNBS administration). This was the same period of time during which there were significant increases in the numbers of monocytes and mast cells within the colonic mucosa. Expression of mRNA for the RANTES receptors, CCR1 and CCR5, was also significantly increased during the chronic phase of colitis. Treatment during this period with Met-RANTES (200 μg/day), an antagonist of the CCR1 and CCR5 receptors (27, 28), resulted in a significant reduction of the severity of colitis and a significant reduction of the numbers of granulocytes, monocytes, and mast cells within the colonic mucosa. Particularly noteworthy was the observation that in four of the six rats treated with the 200 μg/day dose of Met-RANTES, the mucosal ulceration had completely resolved, and there was only mild inflammation limited to the mucosal layer.

Met-RANTES is one of a number of chemokine analogs that act as RANTES antagonists (27, 28, 34). The ability of Met-RANTES to reduce tissue injury in this study is consistent with its effects in models of arthritis (35) and renal inflammation (12). Moreover, a role for RANTES in the progression from acute to chronic colitis, which our results strongly suggest, is consistent with the conclusions of Lloyd et al. (36) with respect to the role of RANTES in murine crescentic nephritis. RANTES could contribute to such a conversion of the inflammatory state by virtue of its chemotactic effects on cells that are involved in chronic inflammation such as monocytes, lymphocytes, and mast cells, in addition to its ability to activate T cells and monocytes (6, 7, 8, 37). RANTES has also been suggested to stimulate neutrophil activation (37), which could contribute to the prolongation of an established inflammatory response, as well as to fibrosis. Moreover, granulocytes have been shown to contribute significantly to acute tissue injury in experimental colitis in rats and rabbits (38, 39, 40). Treatment with Met-RANTES produced a substantial (∼63%) reduction in tissue MPO activity, an index of tissue granulocyte numbers.

The effectiveness of Met-RANTES in abrogating colitis suggests that the CCR1 and/or CCR5 are key receptors in mediating the effects of RANTES in this model. Therefore, it is noteworthy that CCR1 has been implicated in chronic inflammation in other tissues. For example, CCR1 was reported to mediate the gross pulmonary fibrotic response to bleomycin treatment (41). The role of CCR5 in colitis has been examined in a mouse model. The colitis induced by oral administration of dextran sodium sulfate was found to be significantly reduced in mice lacking the gene for CCR5 than in wild-type controls, although there was not any evidence of a reduction in macrophage infiltration into the colon (42). It is also important to note that CCR1 and CCR5 are expressed to differing degrees by various leukocyte subsets. CCR1 has been reported to be expressed on activated T cells, monocytes, eosinophils, dendritic cells, and neutrophils (4, 41, 43). In contrast, CCR5 has been shown to be expressed on activated T cells, monocytes, macrophages, and dendritic cells, but not on neutrophils (41, 43, 44). The expression of CCR1 on neutrophils may account for the earlier increase in expression of this receptor than of CCR5 after induction of colitis because neutrophil recruitment is an early event in the TNBS model.

Although Met-RANTES at a dose of 200 μg/day produced a statistically significant reduction of colonic damage and MPO activity as compared with vehicle-treated controls, it was apparent that this antagonist did not reduce the severity of tissue injury or inflammation in all of the rats that received this agent. The reasons for the apparent failure of response in two of the six rats are not clear. It is possible that these rats had more severe colonic injury at the onset of treatment than the other rats treated with Met-RANTES. Alternatively, it is possible that in some rats, other mediators of inflammation play a more predominant role than RANTES in mediating the progression from acute to chronic colitis. It is noteworthy that heterogeneous responses to therapies are very common in patients with IBD, with 20–40% of patients failing to show a response to the most widely used therapeutic agents (44, 45, 46, 47). Of course, one cannot rule out that possibility that treatment with higher doses of Met-RANTES or treatment over a longer period of time may produce beneficial effects in a higher percentage of rats.

In summary, the results presented herein demonstrate that RANTES expression is markedly elevated in the chronic phase of TNBS-induced colitis in the rat, a time when the expression of a number of other chemokines (MIP-1, MCP-2, CINC) was not significantly elevated above control levels. Expression of two of the key receptors for RANTES was also elevated during the chronic phase of colitis. Moreover, treatment with a CCR1/CCR5 receptor antagonist significantly accelerated the healing of colonic injury, most likely by antagonizing the actions of RANTES. Our results provide novel evidence of a crucial role for RANTES in the progression from acute to chronic colitis in this model. The beneficial effects of RANTES antagonism in experimental colitis suggest that chemokine receptor antagonists are potentially useful therapeutic approaches to the treatment of IBD.

Acknowledgments

We thank Dr. Marcelo Muscara for helpful discussion, and Webb McKnight and Michael Dicay for their assistance in performing these studies.

Footnotes

  • ↵1 This work was supported by a grant from the Medical Research Council of Canada (MRC). Dr. Ajuebor is supported by an Alberta Heritage Foundation for Medical Research (AHFMR) Fellowship. Dr. Wallace is a MRC Senior Scientist and an AHFMR Senior Scientist.

  • ↵2 Address correspondence and reprint requests to Dr. John L. Wallace, Department of Pharmacology and Therapeutics, University of Calgary, 3330 Hospital Drive Northwest, Calgary, Alberta, T2N 4N1, Canada. E-mail address: wallacej{at}ucalgary.ca

  • ↵3 Abbreviations used in this paper: IBD, inflammatory bowel disease; TNBS, trinitrobenzene sulfonic acid; MCP, monocyte chemoattractant protein; CINC, cytokine-induced neutrophil chemoattractant; MPO, myeloperoxidase; MIP, macrophage inflammatory protein.

  • Received June 15, 2000.
  • Accepted October 4, 2000.

References

  1. ↵
    Baggiolini, M.. 1998. Chemokines and leukocyte traffic. Nature 392: 565
    OpenUrlCrossRefPubMed
  2. ↵
    Baggiolini, M., B. Dewald, B. Moser. 1994. Interleukin-8 and related chemotactic cytokines—CXC and CC chemokines. Adv. Immunol. 55: 97
    OpenUrlPubMed
  3. ↵
    Rollins, B. J.. 1997. Chemokines. Blood 90: 909
    OpenUrlFREE Full Text
  4. ↵
    Luster, A. D.. 1998. Chemokines—chemotactic cytokines that mediate inflammation. N. Engl. J. Med. 338: 436
    OpenUrlCrossRefPubMed
  5. ↵
    Proudfoot, A. E., T. N. Wells, P. R. Clapham. 1999. Chemokine receptors—future therapeutic targets for HIV?. Biochem. Pharmacol. 57: 451
    OpenUrlCrossRefPubMed
  6. ↵
    Meurer, R., G. Van Riper, W. Feeney, P. Cunningham, D. Hora, M. S. Springer, D. E. MacIntyre, H. Rosen. 1993. Formation of eosinophilic and monocytic intradermal inflammatory sites in the dog by injection of human RANTES but not human monocyte chemoattractant protein 1, human macrophage inflammatory protein 1α, or human interleukin 8. J. Exp. Med. 178: 1913
    OpenUrlAbstract/FREE Full Text
  7. ↵
    Schall, T. J., K. Bacon, K. J. Toy, D. V. Goeddel. 1990. Selective attraction of monocytes and T lymphocytes of the memory phenotype by cytokine RANTES. Nature 347: 669
    OpenUrlCrossRefPubMed
  8. ↵
    Conti, P., M. Reale, R. C. Barbacane, R. Letourneau, T. C. Theoharides. 1998. Intramuscular injection of hrRANTES causes mast cell recruitment and increased transcription of histidine decarboxylase in mice: lack of effects in genetically mast cell-deficient W/WV mice. FASEB J. 12: 1693
    OpenUrlAbstract/FREE Full Text
  9. ↵
    Das, A. M., M. N. Ajuebor, R. J. Flower, M. Perretti, S. R. McColl. 1999. Contrasting roles for RANTES and macrophage inflammatory protein-1 α (MIP-1α) in a murine model of allergic peritonitis. Clin. Exp. Immunol. 117: 223
    OpenUrlCrossRefPubMed
  10. ↵
    Wells, T. N., A. E. Proudfoot, C. A. Power. 1999. Strategies to interfere with the chemokine network in disease. Chem. Immunol. 72: 181
    OpenUrlCrossRefPubMed
  11. ↵
    Panzer, U., A. Schneider, J. Wilken, D. A. Thompson, S. B. Kent, R. A. Stahl. 1999. The chemokine receptor antagonist AOP-RANTES reduces monocyte infiltration in experimental glomerulonephritis. Kidney Int. 56: 2107
    OpenUrlCrossRefPubMed
  12. ↵
    Grone, H. J., C. Weber, K. S. Weber, E. F. Grone, T. Rabelink, C. M. Klier, T. N. Wells, A. E. Proudfoot, D. Schlondorff, P. J. Nelson. 1999. Met-RANTES reduces vascular and tubular damage during acute renal transplant rejection: blocking monocyte arrest and recruitment. FASEB J. 13: 1371
    OpenUrlAbstract/FREE Full Text
  13. ↵
    Barnes, D. A., J. Tse, M. Kaufhold, M. Owen, J. Hesselgesser, R. Strieter, R. Horuk, H. D. Perez. 1998. Polyclonal antibody directed against human RANTES ameliorates disease in the Lewis rat adjuvant-induced arthritis model. J. Clin. Invest. 101: 2910
    OpenUrlCrossRefPubMed
  14. ↵
    Chensue, S. W., K. S. Warmington, E. J. Allenspach, B. Lu, C. Gerard, S. L. Kunkel, N. W. Lukacs. 1999. Differential expression and cross-regulatory function of RANTES during mycobacterial (type 1) and schistosomal (type 2) antigen-elicited granulomatous inflammation. J. Immunol. 163: 165
    OpenUrlAbstract/FREE Full Text
  15. ↵
    Mazzucchelli, L., C. Hauser, K. Zgraggen, H. E. Wagner, M. W. Hess, J. A. Laissue, C. Mueller. 1996. Differential in situ expression of the genes encoding the chemokines MCP-1 and RANTES in human inflammatory bowel disease. J. Pathol. 178: 201
    OpenUrlCrossRefPubMed
  16. ↵
    McCafferty, D. M., K. A. Sharkey, J. L. Wallace. 1994. Beneficial effects of local or systemic lidocaine in experimental colitis. Am. J. Physiol. 266: G560
    OpenUrlAbstract/FREE Full Text
  17. ↵
    Wallace, J. L., W. K. MacNaughton, G. P. Morris, P. L. Beck. 1989. Inhibition of leukotriene synthesis markedly accelerates healing in a rat model of inflammatory bowel disease. Gastroenterology 96: 29
    OpenUrlPubMed
  18. ↵
    McCafferty, D. M., K. J. Rioux, J. L. Wallace. 1992. Granulocyte infiltration in experimental colitis is interleukin-1 dependent and leukotriene independent. Eicosanoids 5: 121
    OpenUrlPubMed
  19. ↵
    Hogaboam, C. M., K. Jacobson, S.M. Collins, M. G. Blennerhassett. 1995. The selective beneficial effects of nitric oxide inhibition in experimental colitis. Am. J. Physiol. 268: G673
    OpenUrlAbstract/FREE Full Text
  20. ↵
    Mazelin, L., V. Theodorou, J. More, X. Emonds-Alt, J. Fioramonti, L. Bueno. 1998. Comparative effects of nonpeptide tachykinin receptor antagonists on experimental gut inflammation in rats an guinea-pigs. Life Sci. 63: 293
    OpenUrlCrossRefPubMed
  21. ↵
    Neurath, M. F., I. Fuss, M. Pasparakis, L. Alexopoulou, S. Haralambous, K.H. Mayer zum Buschenfelde, W. Strober, G. Kollias. 1997. Predominant pathogenic role of tumor necrosis factor in experimental colitis in mice. Eur. J. Immunol. 27: 1743
    OpenUrlCrossRefPubMed
  22. ↵
    Proudfoot, A. E., R. Buser, F. Borlat, S. Alouani, D. Soler, R. E. Offord, J. M. Schroder, C. A. Power, T. N. Wells. 1999. Amino-terminally modified RANTES analogues demonstrate differential effects on RANTES receptors. J. Biol. Chem. 274: 32478
    OpenUrlAbstract/FREE Full Text
  23. ↵
    Hogaboam, C. M., C. S. Gallinat, D. D. Taub, R. M. Strieter, S. L. Kunkel, N. W. Lukacs. 1999. Immunomodulatory role of C10 chemokine in a murine model of allergic bronchopulmonary aspergillosis. J. Immunol. 162: 6071
    OpenUrlAbstract/FREE Full Text
  24. ↵
    Ferraz, J. G., K. A. Sharkey, B. K. Reuter, S. Asfaha, A. W. Tigley, M. L. Brown, W. McKnight, J. L. Wallace. 1997. Induction of cyclooxygenase 1 and 2 in the rat stomach during endotoxemia: role in resistance to damage. Gastroenterology 113: 195
    OpenUrlCrossRefPubMed
  25. ↵
    Ajuebor, M. N., L. Gibbs, R. J. Flower, A. M. Das, M. Perretti. 1998. Investigation of the functional role played by the chemokine monocyte chemoattractant protein-1 in interleukin-1-induced murine peritonitis. Br. J. Pharmacol. 125: 319
    OpenUrlCrossRefPubMed
  26. ↵
    Boddeke, E. W., I. Meigel, S. Frentzel, N. G. Gourmala, J. K. Harrison, M. Buttini, O. Spleiss, P. Gebicke-Harter. 1999. Cultured rat microglia express functional β-chemokine receptors. J. Neuroimmunol. 98: 176
    OpenUrlCrossRefPubMed
  27. ↵
    Proudfoot, A. E., C. A. Power, A. J. Hoogewerf, M. O. Montjovent, F. Borlat, R. E. Offord, T. N. Wells. 1996. Extension of recombinant human RANTES by the retention of the initiating methionine produces a potent antagonist. J. Biol. Chem. 271: 2599
    OpenUrlAbstract/FREE Full Text
  28. ↵
    Rioux, K. P., J. L. Wallace. 1996. Mast cells do not contribute to nonsteroidal anti-inflammatory drug-induced gastric mucosal injury in rodents. Aliment. Pharmacol. Ther. 10: 173
    OpenUrlCrossRefPubMed
  29. ↵
    Izzo, R. S., K. Witkon, A. I. Chen, C. Hadjiyane, M. I. Weinstein, C. Pellecchia. 1992. Interleukin-8 and neutrophil markers in colonic mucosa from patients with ulcerative colitis. Am. J. Gastroenterol. 87: 1447
    OpenUrlPubMed
  30. ↵
    Morris, G. P., P. L. Beck, M. S. Herridge, W. T. Depew, M. R. Szewczuk, J. L. Wallace. 1989. Hapten-induced model of chronic inflammation and ulceration in the rat colon. Gastroenterology 96: 795
    OpenUrlPubMed
  31. ↵
    Keshavarzian, A., R. D. Fusunyan, M. Jacyno, D. Winship, R. P. MacDermott, I. R. Sanderson. 1999. Increased interleukin-8 (IL-8) in rectal dialysate from patients with ulcerative colitis: evidence for a biological role for IL-8 in inflammation of the colon. Am. J. Gastroenterol. 94: 704
    OpenUrlCrossRefPubMed
  32. ↵
    Reinecker, H. C., E. Y. Loh, D. J. Ringler, A. Mehta, J. L. Rombeau, R. P. MacDermott. 1995. Monocyte-chemoattractant protein 1 gene expression in intestinal epithelial cells and inflammatory bowel disease mucosa. Gastroenterology 108: 40
    OpenUrlCrossRefPubMed
  33. ↵
    Uguccioni, M., P. Gionchetti, D. F. Robbiani, F. Rizzello, S. Peruzzo, M. Campieri, M. Baggiolini. 1999. Increased expression of IP-10, IL-8, MCP-1, and MCP-3 in ulcerative colitis. Am. J. Pathol. 155: 331
    OpenUrlCrossRefPubMed
  34. ↵
    Mosier, D. E., G. R. Picchio, R. J. Gulizia, R. Sabbe, P. Poignard, L. Picard, R. E. Offord, D. A. Thompson, J. Wilken. 1999. Highly potent RANTES analogues either prevent CCR5-using human immunodeficiency virus type I infection in vivo or rapidly select for CXCR4-using variants. J. Virol. 73: 3544
    OpenUrlAbstract/FREE Full Text
  35. ↵
    Plater-Zyberk, C., A. J. Hoogewerf, A. E. Proudfoot, C. A. Power, T. N. C. Wells. 1997. Effect of a CC chemokine receptor antagonist on collagen induced arthritis in DBA/1 mice. Immunol. Lett. 57: 117
    OpenUrlCrossRefPubMed
  36. ↵
    Lloyd, C. M., M. E. Dorf, A. Proudfoot, D. J. Salant, J. C. Gutierrez-Ramos. 1997. Role of MCP-1 and RANTES in inflammation and progression to fibrosis during murine crescentic nephritis. J. Leukocyte Biol. 62: 676
    OpenUrlAbstract
  37. ↵
    Appay, V., A. Brown, S. Cribbes, E. Randle, L. G. Czaplewski. 1999. Aggregation of RANTES is responsible for its inflammatory properties: characterization of nonaggregating, noninflammatory RANTES mutants. J. Biol. Chem. 274: 27505
    OpenUrlAbstract/FREE Full Text
  38. ↵
    Yamada, T., B. J. Zimmerman, R. D. Specian, M. B. Grisham. 1991. Role of neutrophils in acetic acid-induced colitis in rats. Inflammation 15: 399
    OpenUrlCrossRefPubMed
  39. ↵
    Wallace, J. L., A. Higa, G. W. McKnight, D. E. MacIntyre. 1992. Prevention and reversal of experimental colitis by a monoclonal antibody which inhibits leukocyte adherence. Inflammation 16: 343
    OpenUrlCrossRefPubMed
  40. ↵
    Wallace, J. L., W. McKnight, S. Asfaha, D. Y. Liu. 1998. Reduction of acute and reactivated colitis in rats by an inhibitor of neutrophil activation. Am. J. Physiol. 274: G802
    OpenUrlAbstract/FREE Full Text
  41. ↵
    Tokuda, A., M. Itakura, N. Onai, H. Kimura, T. Kuriyama, K. Matsushima. 2000. Pivotal role of CCR1-positive leukocytes in bleomycin-induced lung fibrosis in mice. J. Immunol. 164: 2745
    OpenUrlAbstract/FREE Full Text
  42. ↵
    Andres, P. G., P. L. Beck, E. Mizoguchi, A. Mizoguchi, A. K. Bhan, T. Dawson, W. A. Kuziel, N. Maeda, R. P. MacDermott, D. K. Podolsky, H. C. Reinecker. 2000. Mice with a selective deletion of the CC chemokine receptors 5 or 2 are protected from dextran sodium sulfate-mediated colitis: lack of CC chemokine receptor 5 expression results in a NK1.1+ lymphocyte-associated Th2-type immune response in the intestine. J. Immunol. 164: 6303
    OpenUrlAbstract/FREE Full Text
  43. ↵
    Wells, T. N. C., A. E. I. Proudfoot, C. A. Power. 1999. Strategies to interfere with the chemokine network in disease. Chem. Immunol. 72: 181
    OpenUrlCrossRefPubMed
  44. ↵
    Neote, K., D. Gregorio, J. Y. Mark, R. Horuk, T. J. Schall. 1993. Molecular cloning, functional expression, and signalling characteristics of a C-C chemokine receptor. Cell 72: 415
    OpenUrlCrossRefPubMed
  45. ↵
    Peppercorn, M. A.. 1994. Antiinflammatory agents. S. R. Targan, and F. Shanahan, eds. Inflammatory Bowel Disease: From Bench to Bedside 478 Williams and Wilkins, Baltimore, MD.
  46. ↵
    Andus, T., S. R. Targan. 1994. Glucocorticoids. S. R. Targan, and F. Shanahan, eds. Inflammatory Bowel Disease: From Bench to Bedside 487 Williams and Wilkins, Baltimore, MD.
  47. ↵
    Bernstein, C., F. Shanahan. 1994. Immunomodulatory therapy in inflammmatory bowel disease. S. R. Targan, and F. Shanahan, eds. Inflammatory Bowel Disease: From Bench to Bedside 503 Williams and Wilkins, Baltimore, MD.
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