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An antagonist of monocyte chemoattractant protein 1 (MCP-1) inhibits arthritis in the MRL-lpr mouse model.

Gong JH, Ratkay LG, Waterfield JD, Clark-Lewis I - J. Exp. Med. (1997)

Bottom Line: In contrast, controls treated with native MCP-1 had enhanced arthritis symptoms, indicating that the inhibitory effect is specific to the antagonist.In experiments where the antagonist was given only after the disease had already developed, there was a marked reduction in symptoms and histopathology, although individuals varied in the magnitude of the response.The mechanism of inhibition of disease is not known, although the results suggest that it could be more complex than the competitive inhibition of ligand binding that is observed in vitro.

View Article: PubMed Central - PubMed

Affiliation: Biomedical Research Centre and Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.

ABSTRACT
An antagonist of human monocyte chemoattractant protein (MCP)-1, which consists of MCP-1(9-76), had previously been characterized and shown to inhibit MCP-1 activity in vitro. To test the hypothesis that, by inhibiting endogenous MCP-1, the antagonist has antiinflammatory activity in vivo, we examined its effect in the MRL-lpr mouse model of arthritis. This strain spontaneously develops a chronic inflammatory arthritis that is similar to human rheumatoid arthritis. Daily injection of the antagonist, MCP-1(9-76), prevented the onset of arthritis as monitored by measuring joint swelling and by histopathological evaluation of the joints. In contrast, controls treated with native MCP-1 had enhanced arthritis symptoms, indicating that the inhibitory effect is specific to the antagonist. In experiments where the antagonist was given only after the disease had already developed, there was a marked reduction in symptoms and histopathology, although individuals varied in the magnitude of the response. The mechanism of inhibition of disease is not known, although the results suggest that it could be more complex than the competitive inhibition of ligand binding that is observed in vitro. The demonstration of the beneficial effects of an MCP-1 antagonist in arthritis suggests that chemokine receptor antagonists could have therapeutic application in inflammatory diseases.

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The MCP-1 antagonist prevents the onset of the symptoms  of arthritis. The ankle widths for both hind legs of each animal were measured with a micrometer on the indicated days, and the results are presented as the mean change from the day 0 measurement, ± SEM. *Values  are significantly different from the control MCP-1Ala analogue (P  <0.05). (a) MRL-lpr mice received CFA on day 0 and were injected intraperitoneally daily for 30 d with either MCP-1 antagonist, 2.0 mg/kg,  n = 23, •; MCP-1 antagonist, 0.5 mg/kg, n = 9, ▪; control MCP-1Ala  analogue, 2.0 mg/kg, n = 10, □; or no further treatment, n = 20, ○. (b)  Mice were either injected intravenously daily for 15 d with MCP-1 antagonist, 0.5 mg/kg, n = 6, ▴; or received no further treatment, n = 8,  ○. Results shown are from one of two similar experiments.
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Figure 1: The MCP-1 antagonist prevents the onset of the symptoms of arthritis. The ankle widths for both hind legs of each animal were measured with a micrometer on the indicated days, and the results are presented as the mean change from the day 0 measurement, ± SEM. *Values are significantly different from the control MCP-1Ala analogue (P <0.05). (a) MRL-lpr mice received CFA on day 0 and were injected intraperitoneally daily for 30 d with either MCP-1 antagonist, 2.0 mg/kg, n = 23, •; MCP-1 antagonist, 0.5 mg/kg, n = 9, ▪; control MCP-1Ala analogue, 2.0 mg/kg, n = 10, □; or no further treatment, n = 20, ○. (b) Mice were either injected intravenously daily for 15 d with MCP-1 antagonist, 0.5 mg/kg, n = 6, ▴; or received no further treatment, n = 8, ○. Results shown are from one of two similar experiments.

Mentions: To test the effect of the antagonist on the onset of disease, mice were primed with intradermal CFA on day 0. When the MCP-1 antagonist was given intraperitoneally at a dose of 2.0 mg/kg daily, it resulted in significant reduction of swelling of the ankle joint (Fig. 1 a). Controls that received the same dose of a closely related but inactive analogue, MCP-1Ala, developed similar swelling to that of untreated controls, but showed a trend towards a delayed onset. Although not significant, the effect was likely to be due to the daily injection protocol. In subsequent experiments, the controls were all injected with the control peptide, MCP-1Ala. In a separate experiment where the antagonist treatment was stopped at 15 d (Fig. 1 b), onset was inhibited during the treatment interval, but swelling became apparent by 20 d and rose to untreated control levels by 24 d. Mice that received a fourfold lower intraperitoneal dose of the antagonist did not have a significant reduction in swelling, suggesting that for maximal effect, the concentration of antagonist must be maintained at pharmacological levels. Analysis of the sera for anti MCP-1 antibodies showed that low titers (1:160) were present in both groups (not shown). The production of anti–MCP-1 antibodies was not considered a major factor in these studies.


An antagonist of monocyte chemoattractant protein 1 (MCP-1) inhibits arthritis in the MRL-lpr mouse model.

Gong JH, Ratkay LG, Waterfield JD, Clark-Lewis I - J. Exp. Med. (1997)

The MCP-1 antagonist prevents the onset of the symptoms  of arthritis. The ankle widths for both hind legs of each animal were measured with a micrometer on the indicated days, and the results are presented as the mean change from the day 0 measurement, ± SEM. *Values  are significantly different from the control MCP-1Ala analogue (P  <0.05). (a) MRL-lpr mice received CFA on day 0 and were injected intraperitoneally daily for 30 d with either MCP-1 antagonist, 2.0 mg/kg,  n = 23, •; MCP-1 antagonist, 0.5 mg/kg, n = 9, ▪; control MCP-1Ala  analogue, 2.0 mg/kg, n = 10, □; or no further treatment, n = 20, ○. (b)  Mice were either injected intravenously daily for 15 d with MCP-1 antagonist, 0.5 mg/kg, n = 6, ▴; or received no further treatment, n = 8,  ○. Results shown are from one of two similar experiments.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2198969&req=5

Figure 1: The MCP-1 antagonist prevents the onset of the symptoms of arthritis. The ankle widths for both hind legs of each animal were measured with a micrometer on the indicated days, and the results are presented as the mean change from the day 0 measurement, ± SEM. *Values are significantly different from the control MCP-1Ala analogue (P <0.05). (a) MRL-lpr mice received CFA on day 0 and were injected intraperitoneally daily for 30 d with either MCP-1 antagonist, 2.0 mg/kg, n = 23, •; MCP-1 antagonist, 0.5 mg/kg, n = 9, ▪; control MCP-1Ala analogue, 2.0 mg/kg, n = 10, □; or no further treatment, n = 20, ○. (b) Mice were either injected intravenously daily for 15 d with MCP-1 antagonist, 0.5 mg/kg, n = 6, ▴; or received no further treatment, n = 8, ○. Results shown are from one of two similar experiments.
Mentions: To test the effect of the antagonist on the onset of disease, mice were primed with intradermal CFA on day 0. When the MCP-1 antagonist was given intraperitoneally at a dose of 2.0 mg/kg daily, it resulted in significant reduction of swelling of the ankle joint (Fig. 1 a). Controls that received the same dose of a closely related but inactive analogue, MCP-1Ala, developed similar swelling to that of untreated controls, but showed a trend towards a delayed onset. Although not significant, the effect was likely to be due to the daily injection protocol. In subsequent experiments, the controls were all injected with the control peptide, MCP-1Ala. In a separate experiment where the antagonist treatment was stopped at 15 d (Fig. 1 b), onset was inhibited during the treatment interval, but swelling became apparent by 20 d and rose to untreated control levels by 24 d. Mice that received a fourfold lower intraperitoneal dose of the antagonist did not have a significant reduction in swelling, suggesting that for maximal effect, the concentration of antagonist must be maintained at pharmacological levels. Analysis of the sera for anti MCP-1 antibodies showed that low titers (1:160) were present in both groups (not shown). The production of anti–MCP-1 antibodies was not considered a major factor in these studies.

Bottom Line: In contrast, controls treated with native MCP-1 had enhanced arthritis symptoms, indicating that the inhibitory effect is specific to the antagonist.In experiments where the antagonist was given only after the disease had already developed, there was a marked reduction in symptoms and histopathology, although individuals varied in the magnitude of the response.The mechanism of inhibition of disease is not known, although the results suggest that it could be more complex than the competitive inhibition of ligand binding that is observed in vitro.

View Article: PubMed Central - PubMed

Affiliation: Biomedical Research Centre and Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.

ABSTRACT
An antagonist of human monocyte chemoattractant protein (MCP)-1, which consists of MCP-1(9-76), had previously been characterized and shown to inhibit MCP-1 activity in vitro. To test the hypothesis that, by inhibiting endogenous MCP-1, the antagonist has antiinflammatory activity in vivo, we examined its effect in the MRL-lpr mouse model of arthritis. This strain spontaneously develops a chronic inflammatory arthritis that is similar to human rheumatoid arthritis. Daily injection of the antagonist, MCP-1(9-76), prevented the onset of arthritis as monitored by measuring joint swelling and by histopathological evaluation of the joints. In contrast, controls treated with native MCP-1 had enhanced arthritis symptoms, indicating that the inhibitory effect is specific to the antagonist. In experiments where the antagonist was given only after the disease had already developed, there was a marked reduction in symptoms and histopathology, although individuals varied in the magnitude of the response. The mechanism of inhibition of disease is not known, although the results suggest that it could be more complex than the competitive inhibition of ligand binding that is observed in vitro. The demonstration of the beneficial effects of an MCP-1 antagonist in arthritis suggests that chemokine receptor antagonists could have therapeutic application in inflammatory diseases.

Show MeSH
Related in: MedlinePlus