The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL-4 and IL-10.

Abstract

BACKGROUND AND PURPOSE:

Anti-complement therapies have not been advanced for treating the inflammatory bowel diseases (IBDs) despite a growing body of evidence that blocking C5a protects against induced colitis in rodents. The purpose of this study was to further build on this evidence by examining the efficacy, mechanism and specificity of a potent, non-competitive and orally active C5a receptor (CD88) antagonist, PMX205, in the dextran sulphate sodium (DSS) model of murine innate colitis.

EXPERIMENTAL APPROACH:

Mice with DSS added to their drinking water were orally administered 100 or 200 μg day(-1) PMX205 in prophylactic and therapeutic regimens. Clinical illness, colon histology and local generation of inflammatory mediators were measured to evaluate the impact of PMX205 on disease.

KEY RESULTS:

PMX205 significantly prevented DSS-induced colon inflammation in both regimens, associated with lower pro-inflammatory cytokine production and nitrotyrosine staining in colon sections. Additionally, the levels of anti-inflammatory cytokines IL-4 and IL-10 were increased. PMX205 had no significant effect on C5a levels. The beneficial effect of PMX205 was seen in two strains of mice of differing sensitivities to DSS inflammation, but was inactive in mice lacking CD88.

CONCLUSIONS AND IMPLICATIONS:

Pharmacological inhibition of C5a activity by PMX205 is efficacious in preventing DSS-induced colitis, providing further evidence that targeting CD88 in IBD patients could be a valuable therapeutic option.

• Authors: U Jain, T M Woodruff, A W Stadnyk
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 168 Issue 2 Pg. 488-501 (Jan 2013) ISSN: 1476-5381 [Electronic] England
• PMID: 22924972 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

Chemical References

• Anti-Inflammatory Agents
• Cytokines
• Peptides, Cyclic
• Receptor, Anaphylatoxin C5a
• hydrocinnamate-cyclo(ornithyl-prolyl-cyclohexylalanyl-tryptophyl-arginyl)
• Complement C3a
• Complement C5a
• Dextran Sulfate

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Colitis (chemically induced, drug therapy, immunology, pathology)
• Complement C3a (immunology)
• Complement C5a (immunology)
• Cytokines (immunology)
• Dextran Sulfate
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Peptides, Cyclic (pharmacology, therapeutic use)
• Receptor, Anaphylatoxin C5a (antagonists & inhibitors, genetics)