A Potent and Selective Nonpeptide Antagonist of CXCR2 Inhibits Acute and Chronic Models of Arthritis in the Rabbit

• DOI: 10.4049/jimmunol.169.11.6435
• Publication Date: 2014-04-20T23:41:24Z
• Authors: Patricia L Podolin; Brian J Bolognese; James J Foley; Dulcie B Schmidt; Peter T Buckley; Katherine L Widdo...; Qi Jin; John R White; Judithann M Lee; Richard B Goodman; Tonja R Hagen; Osamu Kajikawa; Lisa A Marshall; Douglas W P Hay; Henry M Sarau
• Keywords: Rabbit (cipher)

Abstract Much evidence implicates IL-8 as a major mediator of inflammation and joint destruction in rheumatoid arthritis. The effects its related ligands are mediated via two receptors, CXCR1 CXCR2. In the present study, we demonstrate that potent selective nonpeptide antagonist human CXCR2 potently inhibits 125I-labeled binding to, IL-8-induced calcium mobilization by, rabbit (IC50 = 40.5 7.7 nM, respectively), but not >1000 2200 respectively). These data suggest is an appropriate species which to examine anti-inflammatory CXCR2-selective antagonist. acute models arthritis induced by knee injection or LPS, chronic Ag (OVA)-induced model, administration at 25 mg/kg mouth twice day significantly reduced synovial fluid neutrophils, monocytes, lymphocytes. addition, more robust LPS- OVA-induced models, were characterized increased levels proinflammatory mediators fluid, TNF-α, IL-8, PGE2, leukotriene B4, C4 reduced, was erythrocyte sedimentation rate, possibly result observed decreases serum TNF-α levels. vitro, inhibited chemotaxis neutrophils 0.75 nM), suggesting inhibition leukocyte migration into likely mechanism modulates disease.