Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2006 Nov;149(6):666-75.
doi: 10.1038/sj.bjp.0706912. Epub 2006 Oct 3.

Pharmacological blockade of CCR1 ameliorates murine arthritis and alters cytokine networks in vivo

Affiliations

Pharmacological blockade of CCR1 ameliorates murine arthritis and alters cytokine networks in vivo

M Amat et al. Br J Pharmacol. 2006 Nov.

Abstract

Background and purpose: The chemokine receptor CCR1 is a potential target for the treatment of rheumatoid arthritis. To explore the impact of CCR1 blockade in experimental arthritis and the underlying mechanisms, we used J-113863, a non-peptide antagonist of the mouse receptor.

Experimental approach: Compound J-113863 was tested in collagen-induced arthritis (CIA) and three models of acute inflammation; Staphylococcus enterotoxin B (SEB)-induced interleukin-2 (IL-2), delayed-type hypersensitivity (DTH) response, and lipopolysaccharide (LPS)-induced tumour necrosis factoralpha (TNFalpha) production. In the LPS model, CCR1 knockout, adrenalectomised, or IL-10-depleted mice were also used. Production of TNFalpha by mouse macrophages and human synovial membrane samples in vitro were also studied.

Key results: Treatment of arthritic mice with J-113863 improved paw inflammation and joint damage, and dramatically decreased cell infiltration into joints. The compound did not inhibit IL-2 or DTH, but reduced plasma TNFalpha levels in LPS-treated mice. Surprisingly, CCR1 knockout mice produced more TNFalpha than controls in response to LPS, and J-113863 decreased TNFalpha also in CCR1 null mice, indicating that its effect was unrelated to CCR1. Adrenalectomy or neutralisation of IL-10 did not prevent inhibition of TNFalpha production by J-113863. The compound did not inhibit mouse TNFalpha in vitro, but did induce a trend towards increased TNFalpha release in cells from synovial membranes of rheumatoid arthritis patients.

Conclusions and implications: CCR1 blockade improves the development of CIA, probably via inhibition of inflammatory cell recruitment. However, results from both CCR1-deficient mice and human synovial membranes suggest that, in some experimental settings, blocking CCR1 could enhance TNF production.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Pharmacokinetic profile of J-113863 after a single i.p. injection of 3 or 10 mg kg−1 to mice. The values of the area under the curve for each dose during the period studied (AUC0-24) are also shown. Three animals were used for each time point.
Figure 2
Figure 2
Effect of J-113863 on collagen-induced arthritis. DBA-1 mice with established disease received either vehicle (V) or the test drug for 11 days by i.p. route. (a) Effect of J-113863 at 3 mg kg−1 (J-3) and 10 mg kg−1 (J-10) on the clinical manifestations of the disease (arthritic index). (b) Effect of the compound on anti-collagen II antibodies of the IgG1 and IgG2A subtypes, measured at the end of the experiment. Results shown are representative of three independent experiments using seven mice per treatment group. *P<0.05; **P<0.01 vs vehicle, Student's t-test.
Figure 3
Figure 3
Effect of the CCR1 antagonist on paw histology. Microscopic images (× 10 for (a, c); 20 × for (b)) representative of the paw of arthritic mice treated with vehicle or 10 mg kg−1 of J-113863 illustrating the joint space (asterisks), the invasive pannus (arrowheads), and the presence of osteoclasts (arrows). (d) Inhibition of the joint damage score by J-113863 at 3 and 10 mg kg−1 vs vehicle. Results shown are representative of three independent experiments using seven mice per treatment group. *P<0.05 vs vehicle-treated mice, Student's t-test.
Figure 4
Figure 4
Effect of J-113863 on the plasma levels of TNFα (a) and IL-10 (b) at 1.5 h after LPS challenge to Swiss mice. Results are the mean and s.e.m. of three independent experiments, each using five animals per treatment group. *P<0.05, **P<0.01 vs vehicle-treated mice, Student's t-test.
Figure 5
Figure 5
Effect of CCR1 deficiency on the plasma levels of TNFα and IL-10. Control (c) and CCR1 knockout mice (ko) were challenged with saline or LPS; plasma levels of TNFα and IL-10 were analyzed. Results are the means and s.e.m. of three independent experiments, each using five animals/treatment group. *P<0.05 ko vs control mice, Student's t-test.
Figure 6
Figure 6
Effect of vehicle or J-113863 at 10 mg kg−1 on the plasma levels of TNFα (a) and IL-10 (b) in CCR1 ko mice challenged with LPS. Results are the means and s.e.m. of three independent experiments, each using five animals per treatment group. *P<0.05, **P<0.01 vs corresponding vehicle-treated mice, Student's t-test.
Figure 7
Figure 7
Effect of anti-IL-10 treatment on the TNF inhibition by J-113863 in LPS-challenged mice. Mice were treated with an anti-IL-10 antibody or corresponding isotype before the administration or vehicle or compound J-113863 at 10 mg kg1. LPS was injected and plasma contents of TNFα (a) and IL-10 (b) measured. Results shown are representative of two independent experiments using five animals per group. **P<0.01 vs corresponding vehicle-treated mice, Student's t-test.
Figure 8
Figure 8
Involvement of the HPA axis in the effect of J-113863 on TNFα and IL-10. Adrenalectomized or sham-operated mice received vehicle (V) or 10 mg kg−1 of J-113863 (J) or rolipram (also 10 mg kg−1; R) followed, half an hour later, by an LPS challenge. Results shown are representative of two independent experiments using five animals per group. *P<0.05, **P<0.01 vs corresponding vehicle-treated mice, Student's t-test.

Similar articles

Cited by

References

    1. Anders H, Belemezova E, Eis S, Segerer S, Vielhauer V, Perez de Lerma G, et al. Late onset of treatment with a chemokine receptor CCR1 antagonist prevents progression of lupus nephritis in MRL-Fas(lpr) mice. J Am Soc Nephro. 2004;15:1504–1513. - PubMed
    1. Anders H, Vielhauer V, Frink M, Linde Y, Cohen C, Blattner SM, et al. A chemokine receptor CCR-1 antagonist reduces renal fibrosis after unilateral ureter ligation. J Clin Inves. 2002;109:251–259. - PMC - PubMed
    1. Blease K, Mehrad B, Standiford T, Lukacs N, Kunkel S, Chensue S, et al. Airway remodeling is absent in CCR1−/− mice during chronic fungal allergic airway disease. J Immunol. 2000;165:1564–1572. - PubMed
    1. Branger J, Van Den Blink B, Weijer S, Madwed J, Bos C, Gupta A, et al. Anti-inflammatory effects of a p38 mitogen-activated protein kinase inhibitor during human endotoxemia. J Immunol. 2002;168:4070–4077. - PubMed
    1. Carpenter K, Ewing J, Schuh J, Ness T, Kunkel S, Aparici M, et al. Therapeutic targeting of CCR1 attenuates established chronic fungal asthma in mice. Br J Pharmacol. 2005;145:1160–1172. - PMC - PubMed

Publication types