Blockade of the chemokine receptor CXCR2 ameliorates adjuvant-induced arthritis in rats

M. M. Barsante, T. M. Cunha, M. Allegretti, F. Cattani, F. Policani, C. Bizzarri, W. L. Tafuri, S. Poole, F. Q. Cunha, R. Bertini, M. M. Teixeira

Research output: Contribution to journalArticle

Abstract

Background and purpose: Chemokine receptors CXCR1 and CXCR2 may mediate influx of neutrophils in models of acute and chronic inflammation. The potential benefits of oral administration of a CXCR1/2 inhibitor, DF 2162, in adjuvant-induced polyarthritis (AIA) were investigated. Experimental approach: A model of AIA in rats was used to compare the therapeutic effects of the treatment with DF2162, anti-TNF or anti-CINC-1 antibodies on joint inflammation and local production of cytokines and chemokines. Key results: DF2162 prevented chemotaxis of rat and human neutrophils induced by chemokines acting on CXCR1/2. DF2162 was orally bioavailable and metabolized to two major metabolites. Only metabolite 1 retained CXCR1/2 blocking activity. Treatment with DF2162 (15 mg kg -1, twice daily) or metabolite 1, but not metabolite 2, starting on day 10 after arthritis induction diminished histological score, the increase in paw volume, neutrophil influx and local production of TNF, IL-1β, CCL2 and CCL5. The effects of DF2162 were similar to those of anti-TNF, and more effective than those of anti-CINC-1, antibodies. DF2162 prevented disease progression even when started 13 days after arthritis induction. Conclusions and implications: DF 2162, a novel orally-active non-competitive allosteric inhibitor of CXCR1 and CXCR2, significantly ameliorates AIA in rats, an effect quantitatively and qualitatively similar to those of anti-TNF antibody treatment. These findings highlight the contribution of CXCR2 in the pathophysiology of AIA and suggest that blockade of CXCR1/2 may be a valid therapeutic target for further studies aiming at the development of new drugs for treatment of rheumatoid arthritis.

Original languageEnglish
Pages (from-to)992-1002
Number of pages11
JournalBritish Journal of Pharmacology
Volume153
Issue number5
DOIs
Publication statusPublished - Mar 2008

Fingerprint

Experimental Arthritis
Chemokine Receptors
Arthritis
Neutrophils
Chemokines
Inflammation
Therapeutics
4-(2-amino-1-methyl-2-oxoethyl)phenyl trifluoromethanesulfonate
Antibodies
Therapeutic Uses
Chemotaxis
Interleukin-1
Oral Administration
Disease Progression
Anti-Idiotypic Antibodies
Rheumatoid Arthritis
Joints
Cytokines

Keywords

  • Chemokine receptor
  • CXCR2
  • Experimental arthritis
  • Neutrophil
  • Rheumatoid arthritis
  • TNF-α

ASJC Scopus subject areas

  • Pharmacology

Cite this

Barsante, M. M., Cunha, T. M., Allegretti, M., Cattani, F., Policani, F., Bizzarri, C., ... Teixeira, M. M. (2008). Blockade of the chemokine receptor CXCR2 ameliorates adjuvant-induced arthritis in rats. British Journal of Pharmacology, 153(5), 992-1002. https://doi.org/10.1038/sj.bjp.0707462

Blockade of the chemokine receptor CXCR2 ameliorates adjuvant-induced arthritis in rats. / Barsante, M. M.; Cunha, T. M.; Allegretti, M.; Cattani, F.; Policani, F.; Bizzarri, C.; Tafuri, W. L.; Poole, S.; Cunha, F. Q.; Bertini, R.; Teixeira, M. M.

In: British Journal of Pharmacology, Vol. 153, No. 5, 03.2008, p. 992-1002.

Research output: Contribution to journalArticle

Barsante, MM, Cunha, TM, Allegretti, M, Cattani, F, Policani, F, Bizzarri, C, Tafuri, WL, Poole, S, Cunha, FQ, Bertini, R & Teixeira, MM 2008, 'Blockade of the chemokine receptor CXCR2 ameliorates adjuvant-induced arthritis in rats', British Journal of Pharmacology, vol. 153, no. 5, pp. 992-1002. https://doi.org/10.1038/sj.bjp.0707462
Barsante, M. M. ; Cunha, T. M. ; Allegretti, M. ; Cattani, F. ; Policani, F. ; Bizzarri, C. ; Tafuri, W. L. ; Poole, S. ; Cunha, F. Q. ; Bertini, R. ; Teixeira, M. M. / Blockade of the chemokine receptor CXCR2 ameliorates adjuvant-induced arthritis in rats. In: British Journal of Pharmacology. 2008 ; Vol. 153, No. 5. pp. 992-1002.
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abstract = "Background and purpose: Chemokine receptors CXCR1 and CXCR2 may mediate influx of neutrophils in models of acute and chronic inflammation. The potential benefits of oral administration of a CXCR1/2 inhibitor, DF 2162, in adjuvant-induced polyarthritis (AIA) were investigated. Experimental approach: A model of AIA in rats was used to compare the therapeutic effects of the treatment with DF2162, anti-TNF or anti-CINC-1 antibodies on joint inflammation and local production of cytokines and chemokines. Key results: DF2162 prevented chemotaxis of rat and human neutrophils induced by chemokines acting on CXCR1/2. DF2162 was orally bioavailable and metabolized to two major metabolites. Only metabolite 1 retained CXCR1/2 blocking activity. Treatment with DF2162 (15 mg kg -1, twice daily) or metabolite 1, but not metabolite 2, starting on day 10 after arthritis induction diminished histological score, the increase in paw volume, neutrophil influx and local production of TNF, IL-1β, CCL2 and CCL5. The effects of DF2162 were similar to those of anti-TNF, and more effective than those of anti-CINC-1, antibodies. DF2162 prevented disease progression even when started 13 days after arthritis induction. Conclusions and implications: DF 2162, a novel orally-active non-competitive allosteric inhibitor of CXCR1 and CXCR2, significantly ameliorates AIA in rats, an effect quantitatively and qualitatively similar to those of anti-TNF antibody treatment. These findings highlight the contribution of CXCR2 in the pathophysiology of AIA and suggest that blockade of CXCR1/2 may be a valid therapeutic target for further studies aiming at the development of new drugs for treatment of rheumatoid arthritis.",
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AU - Barsante, M. M.

AU - Cunha, T. M.

AU - Allegretti, M.

AU - Cattani, F.

AU - Policani, F.

AU - Bizzarri, C.

AU - Tafuri, W. L.

AU - Poole, S.

AU - Cunha, F. Q.

AU - Bertini, R.

AU - Teixeira, M. M.

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N2 - Background and purpose: Chemokine receptors CXCR1 and CXCR2 may mediate influx of neutrophils in models of acute and chronic inflammation. The potential benefits of oral administration of a CXCR1/2 inhibitor, DF 2162, in adjuvant-induced polyarthritis (AIA) were investigated. Experimental approach: A model of AIA in rats was used to compare the therapeutic effects of the treatment with DF2162, anti-TNF or anti-CINC-1 antibodies on joint inflammation and local production of cytokines and chemokines. Key results: DF2162 prevented chemotaxis of rat and human neutrophils induced by chemokines acting on CXCR1/2. DF2162 was orally bioavailable and metabolized to two major metabolites. Only metabolite 1 retained CXCR1/2 blocking activity. Treatment with DF2162 (15 mg kg -1, twice daily) or metabolite 1, but not metabolite 2, starting on day 10 after arthritis induction diminished histological score, the increase in paw volume, neutrophil influx and local production of TNF, IL-1β, CCL2 and CCL5. The effects of DF2162 were similar to those of anti-TNF, and more effective than those of anti-CINC-1, antibodies. DF2162 prevented disease progression even when started 13 days after arthritis induction. Conclusions and implications: DF 2162, a novel orally-active non-competitive allosteric inhibitor of CXCR1 and CXCR2, significantly ameliorates AIA in rats, an effect quantitatively and qualitatively similar to those of anti-TNF antibody treatment. These findings highlight the contribution of CXCR2 in the pathophysiology of AIA and suggest that blockade of CXCR1/2 may be a valid therapeutic target for further studies aiming at the development of new drugs for treatment of rheumatoid arthritis.

AB - Background and purpose: Chemokine receptors CXCR1 and CXCR2 may mediate influx of neutrophils in models of acute and chronic inflammation. The potential benefits of oral administration of a CXCR1/2 inhibitor, DF 2162, in adjuvant-induced polyarthritis (AIA) were investigated. Experimental approach: A model of AIA in rats was used to compare the therapeutic effects of the treatment with DF2162, anti-TNF or anti-CINC-1 antibodies on joint inflammation and local production of cytokines and chemokines. Key results: DF2162 prevented chemotaxis of rat and human neutrophils induced by chemokines acting on CXCR1/2. DF2162 was orally bioavailable and metabolized to two major metabolites. Only metabolite 1 retained CXCR1/2 blocking activity. Treatment with DF2162 (15 mg kg -1, twice daily) or metabolite 1, but not metabolite 2, starting on day 10 after arthritis induction diminished histological score, the increase in paw volume, neutrophil influx and local production of TNF, IL-1β, CCL2 and CCL5. The effects of DF2162 were similar to those of anti-TNF, and more effective than those of anti-CINC-1, antibodies. DF2162 prevented disease progression even when started 13 days after arthritis induction. Conclusions and implications: DF 2162, a novel orally-active non-competitive allosteric inhibitor of CXCR1 and CXCR2, significantly ameliorates AIA in rats, an effect quantitatively and qualitatively similar to those of anti-TNF antibody treatment. These findings highlight the contribution of CXCR2 in the pathophysiology of AIA and suggest that blockade of CXCR1/2 may be a valid therapeutic target for further studies aiming at the development of new drugs for treatment of rheumatoid arthritis.

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KW - Neutrophil

KW - Rheumatoid arthritis

KW - TNF-α

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